Bernard Ewigman, MD, MSPH

ILLUSTRATIVE CASE

A 56-year-old man with a history of systolic heart failure and an EF of 30% returns to your clinic for routine follow-up. He reports that he gets mildly short of breath while mowing the lawn, but his condition is stable. He’s already taking an angiotensin-converting enzyme inhibitor (ACEI) and a beta-blocker, and his potassium level is 4.8 mmol/L. Should he also be taking eplerenone?

Heart failure has reached epidemic proportions in the United States.^2-4 Each year, heart failure accounts for more than 1 million hospitalizations,^3,5 and millions more are living with the disease.² ACEIs and beta-blockers are known to decrease hospitalization and mortality for these patients. Recent evidence suggests that mineralocorticoid-receptor antagonists have additional benefits.^2,4,6

Benefits for Class III and IV heart failure are well established
The Randomized Aldactone Evaluation Study (RALES) showed that spironolactone decreased all-cause mortality and hospitalization for cardiovascular causes in patients with Class III and IV heart failure.⁷ In the Ephesus study, the addition of eplerenone to optimal therapy reduced morbidity and mortality in patients with a myocardial infarction (MI) complicated by systolic heart failure.⁸ These studies led to the current guidelines, which recommend using a mineralocorticoid-receptor antagonist for patients with NYHA Class III and IV heart failure, as well as patients with acute MI and either left ventricular dysfunction or heart failure.^2,4,6 Until recently, however, there was no reason to think about using this class of medications for patients with less severe disease.

STUDY SUMMARY: Eplerenone improves outcomes for patients with mild symptoms

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)¹ was a randomized, double-blinded trial designed to evaluate the effect of eplerenone on patients with less severe disease. Eligible patients were older than 55 years, with Class II heart failure and an EF ≤30% (or >30%-35% with a QRS interval >130 ms). Their existing drug regimen had to include an ACEI, angiotensin receptor blocker, or both, as well as a beta-blocker. Patients with a potassium level >5.0 mmol/L, acute MI, or a low glomerular filtration rate (GFR <30 mL/min) were excluded.

Randomization occurred within 6 months of hospitalization for a cardiovascular disorder; study participants without a recent hospitalization were included if they had either a plasma level of B-type natriuretic peptide (BNP) >250 pg/mL or a pro-BNP >500 pg/mL for men or >750 pg/mL for women. A total of 2737 patients were randomized to receive either eplerenone 25 mg/d (the daily dosage was increased to 50 mg after 4 weeks if the potassium level remained <5 mmol/L) or placebo. Patients with an estimated GFR of 30 to 49 mL/min were started on 25 mg eplerenone every other day; if that dose was tolerated, it was increased to 25 mg/d after 4 weeks.

The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure. Secondary outcomes included any hospitalization for heart failure, all-cause mortality, and cardiovascular death.

Patients were evaluated every 4 months. The dose of the eplerenone was decreased if the potassium level was 5.5 to 5.9 mmol/L, and stopped altogether if potassium was >6 mmol/L. Potassium levels were measured within 72 hours of a dosage change, and the drug restarted if potassium levels returned to <5.0 mmol/L.

After 5 months of data collection, 60% of patients in the eplerenone group were on the higher dosage (50 mg/d), as were 65% of the patients receiving placebo. At the conclusion of the trial, the study drug had been discontinued in 16% of patients in the eplerenone group and 17% of the controls.

The primary outcome (death from a cardiovascular cause or hospitalization for heart failure) occurred in 18% of patients in the eplerenone group vs 26% of those on placebo. The number needed to treat to prevent one primary outcome was estimated to be 19 per year of follow-up, and 51 per year of follow-up to postpone one death. The study was terminated early (after a median follow-up of 21 months) due to the clear benefits that were evident in the eplerenone group.

WHAT’S NEW?: We have another way to help Class II patients

Previously, mineralocorticoid-receptor antagonists were recommended only for carefully selected patients—those with a history of MI and heart failure, diabetes and heart failure, or more severe (Class III or IV) heart failure.^4,7 This study shows that heart failure patients with milder symptoms can benefit from eplerenone, as well.

CAVEATS: Cost differential means it pays to try spironolactone first

Eplerenone is expensive (approximately $100 for 30 25-mg tablets at Drugstore.com compared with $4 for the same quantity of spironolactone at Walmart.com). Because eplerenone’s beneficial effects are likely due to its action as a mineralocorticoid-receptor antagonist, it makes sense to use spironolactone as a first-line agent and reserve eplerenone for patients who cannot tolerate it.

Risk of hyperkalemia
Both spironolactone and eplerenone can cause hyperkalemia and should not be used in patients with a baseline potassium level >5.0 mmol/L. Patients who are started on either of these medications should have their potassium levels checked after 3 days, 7 days, and 1 month, then periodically, whenever the dosage is changed.⁴ If the potassium level is >5.0 mmol/L, the dose should be decreased by 50%—and the drug should be stopped if the potassium level is >5.5 mmol/L.¹

In this study, serum potassium levels were >5.5 mmol/L in 12% of patients in the eplerenone group and 7% of those on placebo—a statistically significant difference. Eplerenone therapy was reduced or discontinued in hyperkalemic patients. No one suffered from the significant, but rare, sequelae associated with hyperkalemia, including arrhythmias and sudden death.

Only 2.4% of the patients included in this study were African American (the majority were white, but there was a significant number [11.5%] of Asians). We cannot be sure that African Americans with less severe heart failure would reap the same benefits from treatment with a mineralocorticoid-receptor antagonist.

This was a well-done RCT, which found a significant benefit of eplerenone over placebo. It was a relatively small study, however, and it would help if the findings were replicated in larger studies. It is noteworthy, too, that this study was supported by Pfizer, which manufactures eplerenone, and 2 of the authors were employed by the pharmaceutical company.

CHALLENGES TO IMPLEMENTATION: Close follow-up, lab work is crucial

Hyperkalemia can be a significant side effect of both spironolactone and eplerenone. Patients started on either medication will need close follow-up and frequent lab monitoring of potassium levels. Patients who are unable or unwilling to comply with this strict follow-up are not good candidates for either drug.

Overall, this is a straightforward change to implement. In many cases, convincing patients of the benefits of taking yet another pill will be the greatest challenge. For the right patient population, however, both eplerenone and spironolactone appear to be medications we should encourage more often.

Acknowledgement

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

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 56-year-old man with a history of systolic heart failure and an EF of 30% returns to your clinic for routine follow-up. He reports that he gets mildly short of breath while mowing the lawn, but his condition is stable. He’s already taking an angiotensin-converting enzyme inhibitor (ACEI) and a beta-blocker, and his potassium level is 4.8 mmol/L. Should he also be taking eplerenone?

Heart failure has reached epidemic proportions in the United States.^2-4 Each year, heart failure accounts for more than 1 million hospitalizations,^3,5 and millions more are living with the disease.² ACEIs and beta-blockers are known to decrease hospitalization and mortality for these patients. Recent evidence suggests that mineralocorticoid-receptor antagonists have additional benefits.^2,4,6

Benefits for Class III and IV heart failure are well established
The Randomized Aldactone Evaluation Study (RALES) showed that spironolactone decreased all-cause mortality and hospitalization for cardiovascular causes in patients with Class III and IV heart failure.⁷ In the Ephesus study, the addition of eplerenone to optimal therapy reduced morbidity and mortality in patients with a myocardial infarction (MI) complicated by systolic heart failure.⁸ These studies led to the current guidelines, which recommend using a mineralocorticoid-receptor antagonist for patients with NYHA Class III and IV heart failure, as well as patients with acute MI and either left ventricular dysfunction or heart failure.^2,4,6 Until recently, however, there was no reason to think about using this class of medications for patients with less severe disease.

STUDY SUMMARY: Eplerenone improves outcomes for patients with mild symptoms

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)¹ was a randomized, double-blinded trial designed to evaluate the effect of eplerenone on patients with less severe disease. Eligible patients were older than 55 years, with Class II heart failure and an EF ≤30% (or >30%-35% with a QRS interval >130 ms). Their existing drug regimen had to include an ACEI, angiotensin receptor blocker, or both, as well as a beta-blocker. Patients with a potassium level >5.0 mmol/L, acute MI, or a low glomerular filtration rate (GFR <30 mL/min) were excluded.

Randomization occurred within 6 months of hospitalization for a cardiovascular disorder; study participants without a recent hospitalization were included if they had either a plasma level of B-type natriuretic peptide (BNP) >250 pg/mL or a pro-BNP >500 pg/mL for men or >750 pg/mL for women. A total of 2737 patients were randomized to receive either eplerenone 25 mg/d (the daily dosage was increased to 50 mg after 4 weeks if the potassium level remained <5 mmol/L) or placebo. Patients with an estimated GFR of 30 to 49 mL/min were started on 25 mg eplerenone every other day; if that dose was tolerated, it was increased to 25 mg/d after 4 weeks.

The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure. Secondary outcomes included any hospitalization for heart failure, all-cause mortality, and cardiovascular death.

Patients were evaluated every 4 months. The dose of the eplerenone was decreased if the potassium level was 5.5 to 5.9 mmol/L, and stopped altogether if potassium was >6 mmol/L. Potassium levels were measured within 72 hours of a dosage change, and the drug restarted if potassium levels returned to <5.0 mmol/L.

After 5 months of data collection, 60% of patients in the eplerenone group were on the higher dosage (50 mg/d), as were 65% of the patients receiving placebo. At the conclusion of the trial, the study drug had been discontinued in 16% of patients in the eplerenone group and 17% of the controls.

The primary outcome (death from a cardiovascular cause or hospitalization for heart failure) occurred in 18% of patients in the eplerenone group vs 26% of those on placebo. The number needed to treat to prevent one primary outcome was estimated to be 19 per year of follow-up, and 51 per year of follow-up to postpone one death. The study was terminated early (after a median follow-up of 21 months) due to the clear benefits that were evident in the eplerenone group.

WHAT’S NEW?: We have another way to help Class II patients

Previously, mineralocorticoid-receptor antagonists were recommended only for carefully selected patients—those with a history of MI and heart failure, diabetes and heart failure, or more severe (Class III or IV) heart failure.^4,7 This study shows that heart failure patients with milder symptoms can benefit from eplerenone, as well.

CAVEATS: Cost differential means it pays to try spironolactone first

Eplerenone is expensive (approximately $100 for 30 25-mg tablets at Drugstore.com compared with $4 for the same quantity of spironolactone at Walmart.com). Because eplerenone’s beneficial effects are likely due to its action as a mineralocorticoid-receptor antagonist, it makes sense to use spironolactone as a first-line agent and reserve eplerenone for patients who cannot tolerate it.

Risk of hyperkalemia
Both spironolactone and eplerenone can cause hyperkalemia and should not be used in patients with a baseline potassium level >5.0 mmol/L. Patients who are started on either of these medications should have their potassium levels checked after 3 days, 7 days, and 1 month, then periodically, whenever the dosage is changed.⁴ If the potassium level is >5.0 mmol/L, the dose should be decreased by 50%—and the drug should be stopped if the potassium level is >5.5 mmol/L.¹

In this study, serum potassium levels were >5.5 mmol/L in 12% of patients in the eplerenone group and 7% of those on placebo—a statistically significant difference. Eplerenone therapy was reduced or discontinued in hyperkalemic patients. No one suffered from the significant, but rare, sequelae associated with hyperkalemia, including arrhythmias and sudden death.

Only 2.4% of the patients included in this study were African American (the majority were white, but there was a significant number [11.5%] of Asians). We cannot be sure that African Americans with less severe heart failure would reap the same benefits from treatment with a mineralocorticoid-receptor antagonist.

This was a well-done RCT, which found a significant benefit of eplerenone over placebo. It was a relatively small study, however, and it would help if the findings were replicated in larger studies. It is noteworthy, too, that this study was supported by Pfizer, which manufactures eplerenone, and 2 of the authors were employed by the pharmaceutical company.

CHALLENGES TO IMPLEMENTATION: Close follow-up, lab work is crucial

Hyperkalemia can be a significant side effect of both spironolactone and eplerenone. Patients started on either medication will need close follow-up and frequent lab monitoring of potassium levels. Patients who are unable or unwilling to comply with this strict follow-up are not good candidates for either drug.

Overall, this is a straightforward change to implement. In many cases, convincing patients of the benefits of taking yet another pill will be the greatest challenge. For the right patient population, however, both eplerenone and spironolactone appear to be medications we should encourage more often.

Acknowledgement

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

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 56-year-old man with a history of systolic heart failure and an EF of 30% returns to your clinic for routine follow-up. He reports that he gets mildly short of breath while mowing the lawn, but his condition is stable. He’s already taking an angiotensin-converting enzyme inhibitor (ACEI) and a beta-blocker, and his potassium level is 4.8 mmol/L. Should he also be taking eplerenone?

Heart failure has reached epidemic proportions in the United States.^2-4 Each year, heart failure accounts for more than 1 million hospitalizations,^3,5 and millions more are living with the disease.² ACEIs and beta-blockers are known to decrease hospitalization and mortality for these patients. Recent evidence suggests that mineralocorticoid-receptor antagonists have additional benefits.^2,4,6

Benefits for Class III and IV heart failure are well established
The Randomized Aldactone Evaluation Study (RALES) showed that spironolactone decreased all-cause mortality and hospitalization for cardiovascular causes in patients with Class III and IV heart failure.⁷ In the Ephesus study, the addition of eplerenone to optimal therapy reduced morbidity and mortality in patients with a myocardial infarction (MI) complicated by systolic heart failure.⁸ These studies led to the current guidelines, which recommend using a mineralocorticoid-receptor antagonist for patients with NYHA Class III and IV heart failure, as well as patients with acute MI and either left ventricular dysfunction or heart failure.^2,4,6 Until recently, however, there was no reason to think about using this class of medications for patients with less severe disease.

STUDY SUMMARY: Eplerenone improves outcomes for patients with mild symptoms

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)¹ was a randomized, double-blinded trial designed to evaluate the effect of eplerenone on patients with less severe disease. Eligible patients were older than 55 years, with Class II heart failure and an EF ≤30% (or >30%-35% with a QRS interval >130 ms). Their existing drug regimen had to include an ACEI, angiotensin receptor blocker, or both, as well as a beta-blocker. Patients with a potassium level >5.0 mmol/L, acute MI, or a low glomerular filtration rate (GFR <30 mL/min) were excluded.

Randomization occurred within 6 months of hospitalization for a cardiovascular disorder; study participants without a recent hospitalization were included if they had either a plasma level of B-type natriuretic peptide (BNP) >250 pg/mL or a pro-BNP >500 pg/mL for men or >750 pg/mL for women. A total of 2737 patients were randomized to receive either eplerenone 25 mg/d (the daily dosage was increased to 50 mg after 4 weeks if the potassium level remained <5 mmol/L) or placebo. Patients with an estimated GFR of 30 to 49 mL/min were started on 25 mg eplerenone every other day; if that dose was tolerated, it was increased to 25 mg/d after 4 weeks.

The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure. Secondary outcomes included any hospitalization for heart failure, all-cause mortality, and cardiovascular death.

Patients were evaluated every 4 months. The dose of the eplerenone was decreased if the potassium level was 5.5 to 5.9 mmol/L, and stopped altogether if potassium was >6 mmol/L. Potassium levels were measured within 72 hours of a dosage change, and the drug restarted if potassium levels returned to <5.0 mmol/L.

After 5 months of data collection, 60% of patients in the eplerenone group were on the higher dosage (50 mg/d), as were 65% of the patients receiving placebo. At the conclusion of the trial, the study drug had been discontinued in 16% of patients in the eplerenone group and 17% of the controls.

The primary outcome (death from a cardiovascular cause or hospitalization for heart failure) occurred in 18% of patients in the eplerenone group vs 26% of those on placebo. The number needed to treat to prevent one primary outcome was estimated to be 19 per year of follow-up, and 51 per year of follow-up to postpone one death. The study was terminated early (after a median follow-up of 21 months) due to the clear benefits that were evident in the eplerenone group.

WHAT’S NEW?: We have another way to help Class II patients

Previously, mineralocorticoid-receptor antagonists were recommended only for carefully selected patients—those with a history of MI and heart failure, diabetes and heart failure, or more severe (Class III or IV) heart failure.^4,7 This study shows that heart failure patients with milder symptoms can benefit from eplerenone, as well.

CAVEATS: Cost differential means it pays to try spironolactone first

Eplerenone is expensive (approximately $100 for 30 25-mg tablets at Drugstore.com compared with $4 for the same quantity of spironolactone at Walmart.com). Because eplerenone’s beneficial effects are likely due to its action as a mineralocorticoid-receptor antagonist, it makes sense to use spironolactone as a first-line agent and reserve eplerenone for patients who cannot tolerate it.

Risk of hyperkalemia
Both spironolactone and eplerenone can cause hyperkalemia and should not be used in patients with a baseline potassium level >5.0 mmol/L. Patients who are started on either of these medications should have their potassium levels checked after 3 days, 7 days, and 1 month, then periodically, whenever the dosage is changed.⁴ If the potassium level is >5.0 mmol/L, the dose should be decreased by 50%—and the drug should be stopped if the potassium level is >5.5 mmol/L.¹

In this study, serum potassium levels were >5.5 mmol/L in 12% of patients in the eplerenone group and 7% of those on placebo—a statistically significant difference. Eplerenone therapy was reduced or discontinued in hyperkalemic patients. No one suffered from the significant, but rare, sequelae associated with hyperkalemia, including arrhythmias and sudden death.

Only 2.4% of the patients included in this study were African American (the majority were white, but there was a significant number [11.5%] of Asians). We cannot be sure that African Americans with less severe heart failure would reap the same benefits from treatment with a mineralocorticoid-receptor antagonist.

This was a well-done RCT, which found a significant benefit of eplerenone over placebo. It was a relatively small study, however, and it would help if the findings were replicated in larger studies. It is noteworthy, too, that this study was supported by Pfizer, which manufactures eplerenone, and 2 of the authors were employed by the pharmaceutical company.

CHALLENGES TO IMPLEMENTATION: Close follow-up, lab work is crucial

Hyperkalemia can be a significant side effect of both spironolactone and eplerenone. Patients started on either medication will need close follow-up and frequent lab monitoring of potassium levels. Patients who are unable or unwilling to comply with this strict follow-up are not good candidates for either drug.

Overall, this is a straightforward change to implement. In many cases, convincing patients of the benefits of taking yet another pill will be the greatest challenge. For the right patient population, however, both eplerenone and spironolactone appear to be medications we should encourage more often.

Acknowledgement

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

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 35-year-old woman comes to your office with a headache that has persisted for 24 hours—the typical duration of her migraines, she says. She is nauseated, photophobic, and has a right-sided headache that she rates as moderate to severe. You’ve read about the potential role of corticosteroids in treating acute migraine and wonder whether to add dexamethasone (Decadron) to the standard treatment.

Migraine headaches present a therapeutic challenge: You need to determine which therapeutic regimen is best, not only for immediate relief, but also for its ability to prevent recurrence. With up to two-thirds of migraine patients experiencing another headache within 24 to 48 hours of treatment,¹ many seek repeat treatment within a short time frame.² As such, they’re at risk for medication overuse, which may contribute to an increase in both the intensity and frequency of symptoms.³

A steroid may blunt inflammatory response

The pathogenesis of migraine headache is poorly understood. One theory is that migraines are associated with a neurogenic inflammatory response with the release of vasoactive neuropeptide. This inflammation is thought to be responsible for the initiation and perpetuation of the headache.¹ It therefore follows that the addition of a steroid to standard migraine therapy may blunt this inflammatory response. Several small studies have investigated this possibility, but they had inadequate power to detect a meaningful difference. The meta-analysis detailed in this PURL makes a stronger case.

STUDY SUMMARY: Only 1 steroid studied, but it delivered

Singh and colleagues performed a systematic search for randomized controlled trials (RCTs) studying the use of corticosteroids in the emergency department (ED) as a treatment adjunct for migraine headache.¹ They used rigorous search methods and well-defined inclusion criteria. The primary outcome of interest was the proportion of migraine patients who reported symptoms of moderate or severe headache at 24- to 72-hour follow-up.

Seven studies, with a total of 742 patients, met the inclusion criteria. All were RCTs in which participants and providers were blinded to treatment assignments, and all involved the addition of dexamethasone. No studies evaluating other steroids were found in the literature review. The patients were all diagnosed as having acute migraine headache by the ED physician, based on International Headache Society criteria.⁴

The adjunctive therapy—dexamethasone or placebo—was initiated in the ED, in addition to routine treatment. The standard migraine treatment was not the same for all the RCTs and was based on physician choice. Routinely used medications included metoclopramide (Reglan), ketorolac (Toradol), chlorpromazine (Compazine), and diphenhydramine (Benadryl). Doses of dexamethasone also varied, ranging from 8 to 24 mg; the median dose was 15 mg. All studies cited the proportion of migraine patients who had self-reported moderate to severe headache at 24 to 72 hours after treatment.

Dexamethasone prevents 1 recurrence in 10. The meta-analysis revealed a moderate benefit when dexamethasone was added to standard therapy for migraine headache in the ED. The addition of dexamethasone to standard migraine therapy prevented almost 1 in 10 patients from experiencing moderate to severe recurrent headache in 24 to 72 hours (relative risk [RR]=0.87, 95% confidence interval [CI], 0.80-0.95). Transient side effects occurred in about 25% of patients in both the treatment and placebo groups.

Sensitivity analysis indicated that this meta-analysis was fairly robust, with no single trial dominating the results. There was no evidence of missing studies due to publication bias. These results are consistent with a similar meta-analysis, which also included 7 studies, all but 1 of which were the same.⁵

WHAT’S NEW?: Earlier findings gain strength in numbers

This meta-analysis demonstrates that adjunctive therapy with a steroid is a viable option in the management of acute migraines—an intervention that each of the individual 7 RCTs was too small to justify on its own. Specifically, the addition of dexamethasone to standard migraine treatment may prevent severe recurrent pain that would otherwise necessitate a repeat visit to the ED—or to your office.

CAVEATS: Will it work in an office setting?

This meta-analysis addresses more severe headache recurrences, which are likely to lead patients to seek additional medication or repeat evaluation. Indeed, all 7 RCTs included in the evaluation were performed in an ED setting. And 6 of the 7 trials assessed dexamethasone administered parenterally, which may not be possible in some office settings. In the single trial in which the steroid was administered orally, patients were given 8 mg dexamethasone in addition to intravenous phenothiazines. In the 63 patients included in that study, the relative risk of recurrent headache was 0.69 (95% CI, 0.33-1.45). However, among those with a headache duration of <24 hours (n=40, 63.5%), the relative risk was 0.33 (95% CI, 0.11-1.05).⁶

Other questions: It is not clear from this single trial whether oral dexamethasone is as effective as IV administration. Nor is it clear whether other corticosteroids will work as well, as no studies of other agents have been reported.^1,5 The lowest effective dose of dexamethasone is also not known.

BARRIERS TO IMPLEMENTATION: Repeat steroid use raises risk of complications

Based on this meta-analysis, it is unclear whether IV administration is required for the desired benefit. Another potential concern is associated with the administration of frequent dexamethasone boluses in patients with frequent migraines, which could lead to any one of a number of steroid-related adverse reactions, including osteonecrosis.⁷ The risks of steroid-related complications should be considered in using this therapy, especially for patients receiving multiple doses of dexamethasone.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR02499 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 35-year-old woman comes to your office with a headache that has persisted for 24 hours—the typical duration of her migraines, she says. She is nauseated, photophobic, and has a right-sided headache that she rates as moderate to severe. You’ve read about the potential role of corticosteroids in treating acute migraine and wonder whether to add dexamethasone (Decadron) to the standard treatment.

Migraine headaches present a therapeutic challenge: You need to determine which therapeutic regimen is best, not only for immediate relief, but also for its ability to prevent recurrence. With up to two-thirds of migraine patients experiencing another headache within 24 to 48 hours of treatment,¹ many seek repeat treatment within a short time frame.² As such, they’re at risk for medication overuse, which may contribute to an increase in both the intensity and frequency of symptoms.³

A steroid may blunt inflammatory response

The pathogenesis of migraine headache is poorly understood. One theory is that migraines are associated with a neurogenic inflammatory response with the release of vasoactive neuropeptide. This inflammation is thought to be responsible for the initiation and perpetuation of the headache.¹ It therefore follows that the addition of a steroid to standard migraine therapy may blunt this inflammatory response. Several small studies have investigated this possibility, but they had inadequate power to detect a meaningful difference. The meta-analysis detailed in this PURL makes a stronger case.

STUDY SUMMARY: Only 1 steroid studied, but it delivered

Singh and colleagues performed a systematic search for randomized controlled trials (RCTs) studying the use of corticosteroids in the emergency department (ED) as a treatment adjunct for migraine headache.¹ They used rigorous search methods and well-defined inclusion criteria. The primary outcome of interest was the proportion of migraine patients who reported symptoms of moderate or severe headache at 24- to 72-hour follow-up.

Seven studies, with a total of 742 patients, met the inclusion criteria. All were RCTs in which participants and providers were blinded to treatment assignments, and all involved the addition of dexamethasone. No studies evaluating other steroids were found in the literature review. The patients were all diagnosed as having acute migraine headache by the ED physician, based on International Headache Society criteria.⁴

The adjunctive therapy—dexamethasone or placebo—was initiated in the ED, in addition to routine treatment. The standard migraine treatment was not the same for all the RCTs and was based on physician choice. Routinely used medications included metoclopramide (Reglan), ketorolac (Toradol), chlorpromazine (Compazine), and diphenhydramine (Benadryl). Doses of dexamethasone also varied, ranging from 8 to 24 mg; the median dose was 15 mg. All studies cited the proportion of migraine patients who had self-reported moderate to severe headache at 24 to 72 hours after treatment.

Dexamethasone prevents 1 recurrence in 10. The meta-analysis revealed a moderate benefit when dexamethasone was added to standard therapy for migraine headache in the ED. The addition of dexamethasone to standard migraine therapy prevented almost 1 in 10 patients from experiencing moderate to severe recurrent headache in 24 to 72 hours (relative risk [RR]=0.87, 95% confidence interval [CI], 0.80-0.95). Transient side effects occurred in about 25% of patients in both the treatment and placebo groups.

Sensitivity analysis indicated that this meta-analysis was fairly robust, with no single trial dominating the results. There was no evidence of missing studies due to publication bias. These results are consistent with a similar meta-analysis, which also included 7 studies, all but 1 of which were the same.⁵

WHAT’S NEW?: Earlier findings gain strength in numbers

This meta-analysis demonstrates that adjunctive therapy with a steroid is a viable option in the management of acute migraines—an intervention that each of the individual 7 RCTs was too small to justify on its own. Specifically, the addition of dexamethasone to standard migraine treatment may prevent severe recurrent pain that would otherwise necessitate a repeat visit to the ED—or to your office.

CAVEATS: Will it work in an office setting?

This meta-analysis addresses more severe headache recurrences, which are likely to lead patients to seek additional medication or repeat evaluation. Indeed, all 7 RCTs included in the evaluation were performed in an ED setting. And 6 of the 7 trials assessed dexamethasone administered parenterally, which may not be possible in some office settings. In the single trial in which the steroid was administered orally, patients were given 8 mg dexamethasone in addition to intravenous phenothiazines. In the 63 patients included in that study, the relative risk of recurrent headache was 0.69 (95% CI, 0.33-1.45). However, among those with a headache duration of <24 hours (n=40, 63.5%), the relative risk was 0.33 (95% CI, 0.11-1.05).⁶

Other questions: It is not clear from this single trial whether oral dexamethasone is as effective as IV administration. Nor is it clear whether other corticosteroids will work as well, as no studies of other agents have been reported.^1,5 The lowest effective dose of dexamethasone is also not known.

BARRIERS TO IMPLEMENTATION: Repeat steroid use raises risk of complications

Based on this meta-analysis, it is unclear whether IV administration is required for the desired benefit. Another potential concern is associated with the administration of frequent dexamethasone boluses in patients with frequent migraines, which could lead to any one of a number of steroid-related adverse reactions, including osteonecrosis.⁷ The risks of steroid-related complications should be considered in using this therapy, especially for patients receiving multiple doses of dexamethasone.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR02499 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 35-year-old woman comes to your office with a headache that has persisted for 24 hours—the typical duration of her migraines, she says. She is nauseated, photophobic, and has a right-sided headache that she rates as moderate to severe. You’ve read about the potential role of corticosteroids in treating acute migraine and wonder whether to add dexamethasone (Decadron) to the standard treatment.

Migraine headaches present a therapeutic challenge: You need to determine which therapeutic regimen is best, not only for immediate relief, but also for its ability to prevent recurrence. With up to two-thirds of migraine patients experiencing another headache within 24 to 48 hours of treatment,¹ many seek repeat treatment within a short time frame.² As such, they’re at risk for medication overuse, which may contribute to an increase in both the intensity and frequency of symptoms.³

A steroid may blunt inflammatory response

The pathogenesis of migraine headache is poorly understood. One theory is that migraines are associated with a neurogenic inflammatory response with the release of vasoactive neuropeptide. This inflammation is thought to be responsible for the initiation and perpetuation of the headache.¹ It therefore follows that the addition of a steroid to standard migraine therapy may blunt this inflammatory response. Several small studies have investigated this possibility, but they had inadequate power to detect a meaningful difference. The meta-analysis detailed in this PURL makes a stronger case.

STUDY SUMMARY: Only 1 steroid studied, but it delivered

Singh and colleagues performed a systematic search for randomized controlled trials (RCTs) studying the use of corticosteroids in the emergency department (ED) as a treatment adjunct for migraine headache.¹ They used rigorous search methods and well-defined inclusion criteria. The primary outcome of interest was the proportion of migraine patients who reported symptoms of moderate or severe headache at 24- to 72-hour follow-up.

Seven studies, with a total of 742 patients, met the inclusion criteria. All were RCTs in which participants and providers were blinded to treatment assignments, and all involved the addition of dexamethasone. No studies evaluating other steroids were found in the literature review. The patients were all diagnosed as having acute migraine headache by the ED physician, based on International Headache Society criteria.⁴

The adjunctive therapy—dexamethasone or placebo—was initiated in the ED, in addition to routine treatment. The standard migraine treatment was not the same for all the RCTs and was based on physician choice. Routinely used medications included metoclopramide (Reglan), ketorolac (Toradol), chlorpromazine (Compazine), and diphenhydramine (Benadryl). Doses of dexamethasone also varied, ranging from 8 to 24 mg; the median dose was 15 mg. All studies cited the proportion of migraine patients who had self-reported moderate to severe headache at 24 to 72 hours after treatment.

Dexamethasone prevents 1 recurrence in 10. The meta-analysis revealed a moderate benefit when dexamethasone was added to standard therapy for migraine headache in the ED. The addition of dexamethasone to standard migraine therapy prevented almost 1 in 10 patients from experiencing moderate to severe recurrent headache in 24 to 72 hours (relative risk [RR]=0.87, 95% confidence interval [CI], 0.80-0.95). Transient side effects occurred in about 25% of patients in both the treatment and placebo groups.

Sensitivity analysis indicated that this meta-analysis was fairly robust, with no single trial dominating the results. There was no evidence of missing studies due to publication bias. These results are consistent with a similar meta-analysis, which also included 7 studies, all but 1 of which were the same.⁵

WHAT’S NEW?: Earlier findings gain strength in numbers

This meta-analysis demonstrates that adjunctive therapy with a steroid is a viable option in the management of acute migraines—an intervention that each of the individual 7 RCTs was too small to justify on its own. Specifically, the addition of dexamethasone to standard migraine treatment may prevent severe recurrent pain that would otherwise necessitate a repeat visit to the ED—or to your office.

CAVEATS: Will it work in an office setting?

This meta-analysis addresses more severe headache recurrences, which are likely to lead patients to seek additional medication or repeat evaluation. Indeed, all 7 RCTs included in the evaluation were performed in an ED setting. And 6 of the 7 trials assessed dexamethasone administered parenterally, which may not be possible in some office settings. In the single trial in which the steroid was administered orally, patients were given 8 mg dexamethasone in addition to intravenous phenothiazines. In the 63 patients included in that study, the relative risk of recurrent headache was 0.69 (95% CI, 0.33-1.45). However, among those with a headache duration of <24 hours (n=40, 63.5%), the relative risk was 0.33 (95% CI, 0.11-1.05).⁶

Other questions: It is not clear from this single trial whether oral dexamethasone is as effective as IV administration. Nor is it clear whether other corticosteroids will work as well, as no studies of other agents have been reported.^1,5 The lowest effective dose of dexamethasone is also not known.

BARRIERS TO IMPLEMENTATION: Repeat steroid use raises risk of complications

Based on this meta-analysis, it is unclear whether IV administration is required for the desired benefit. Another potential concern is associated with the administration of frequent dexamethasone boluses in patients with frequent migraines, which could lead to any one of a number of steroid-related adverse reactions, including osteonecrosis.⁷ The risks of steroid-related complications should be considered in using this therapy, especially for patients receiving multiple doses of dexamethasone.

Acknowledgements

The PURLs Surveillance System is supported in part by Grant Number UL1RR02499 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Last month, we introduced you to 15-year-old Jane, a teenager whose once bubbly personality had in the last few months been reduced to a mood of quiet sadness. Her responses to your questions were muted, unenthusiastic. While Jane gets to school every day and can often shake off her down mood when she’s with friends, her responses to the Kutcher Adolescent Depression scale suggest that she’s struggling. You conclude that Jane is experiencing an episode of mild depressive disorder.

How would you manage Jane’s case? And what would you do if her symptoms worsened?

What’s the preference of patient and family?

Begin your initial management of a patient like Jane by considering the treatment preferences of the patient and her family, the severity and urgency of the case, the availability of mental health services, and your own comfort level with managing mental health disorders. A key conclusion of the GLAD-PC (GuideLines for Adolescent Depression in Primary Care) collaborative, described in Part 1 of this series, was that family physicians, alone or in collaboration with mental health professionals, are competent to manage adolescent depression.¹ You may or may not choose to manage a patient like Jane yourself, but even if you refer, your initial management provides an essential bridge until the patient and her family are seen by mental health professionals.

Your initial management should include the following:

• education
• a treatment plan
• safety planning.

Step 1: Educate patient and parents

Help your patient to better understand what it means to have depression. Describe the signs and symptoms that led to the diagnosis of depression and review the natural history of the illness, including the chronic nature of the disorder and its tendency to recur. Explain, too, the impact that depression can have on different areas of functioning, such as school performance and peer relationships, and then review the treatment options. You or someone on your staff can provide this patient education initially, but it is also critical to connect the family to specific community resources for additional education, advocacy, and peer support.¹

To do this effectively, you need to establish links with mental health resources in the community, including mental health service providers, as well as patients and families who have dealt with adolescent depression and are willing to serve as resources to other teens and their families. The GLAD-PC toolkit, available at www.gladpc.org, provides patient education handouts and links to reputable Web sites, advocacy organizations, and peer support groups. Additional online resources are listed in TABLE 1.

TABLE 1
Online resources

Step 2: Work out a treatment plan

Developing a treatment plan that the patient and her parents can accept is critical. A plan that includes psychotherapy with a mental health provider, for example, won’t be acceptable to some patients and parents. They may refuse to participate, or their underlying mistrust may affect the outcome of treatment.^2,3 Other families may reject any therapeutic approach that includes psychotropic drugs.

Expectations about the benefits of treatment influence outcomes significantly, so that, too, is a topic to explore as the treatment plan is worked out.^3,4 Finally, the plan should include agreed-upon goals of treatment. For Jane, planned goals might include getting back into gymnastics or trying out for the school play.

Step 3: Plan for safety

Suicidality, including ideation, behaviors, or attempts, is common among adolescents with depression.^5,6 In studies of completed suicide, more than 50% of the victims had a diagnosis of depression.⁵ To keep your patient safe, develop an emergency communication mechanism for handling increased suicidality or acute crises. If the patient’s risk is high, as shown by a clear plan or intent, immediate hospitalization may be necessary.

If you determine that inpatient treatment is not needed, you need to be sure that adequate adult supervision and support are available; that the teenager does not have access to potentially lethal medications, knives and other sharp objects, or firearms; and that both the patient and parents understand that drugs and alcohol weaken inhibitions. You need to set up a contingency plan with the family that includes checking in with you at reasonable intervals to assure the teen’s safety.⁵

Establishing a safety plan is especially important during the period of diagnosis and initial treatment, when suicide risk is highest.⁶ Confidentiality is the norm in adolescent medicine, but a patient like Jane must understand that you will breach confidentiality if that is necessary to keep her safe from harm.

Treatment options: When active support is best

Selecting the appropriate treatment modality for your patient hinges, of course, on the severity of the teen’s depression. (For more information on how to determine the severity of a depressive episode, see the first installment of this series, “Adolescent depression: Is your young patient suffering in silence?” J Fam Pract. 2009;58:187-192.)

When caring for a patient like Jane who is suffering from mild depression, consider providing active support and monitoring during 6 to 8 weekly or biweekly visits before recommending antidepressant medication or psychotherapy. This approach is also indicated when depressed patients or their parents refuse other treatments.⁷

Active support and monitoring may include education, frequent follow-up, a prescribed regimen of exercise and leisure activities, referral to a peer support group, and review of self-management goals. Other resources for active monitoring can be found in the GLAD-PC toolkit (available at www.gladpc.org). Evidence from randomized controlled trials (RCTs) shows that a sizable percentage of young people with depression respond to nondirective supportive therapy and regular symptom monitoring.⁷ Furthermore, emerging data from the research literature, expert opinion, and patient and family preferences indicate that active support and monitoring from family physicians is an important therapeutic strategy.^7,8

Is therapy needed—and if so, what kind?

Adolescents with moderate or severe depression or patients with mild depression whose symptoms do not improve with active support and monitoring alone will likely require treatment with one of the evidenced-based treatments, such as psychotherapy or antidepressants. Referral to a mental health provider for further assessment or treatment may also be required, depending on the training of the physician.^7,8 If so, you and the mental health provider will need to negotiate your roles and responsibilities for ongoing management, with the input and approval of the patient and family.

Both cognitive behavioral therapy (CBT) and interpersonal therapy (IPT) have been adapted to address major depressive disorder (MDD) in adolescents and have been shown to be effective in community as well as specialized settings.^9-11

CBT is time-limited and delivered individually or by 1 or 2 clinicians working with a group. Clinicians follow a manual to guide each session.¹² (A manual for therapists and a workbook for adolescents and parents can be downloaded from the Kaiser Permanente Center for Health Research Web site at http://www.kpchr.org/public/acwd/acwd.html.)

The focus of CBT is to change patients’ perception of themselves, their world, and others. CBT treats depression by identifying behavioral and cognitive patterns associated with depressive cycles. Examples of such patterns include the propensity to withdraw from pleasurable activities, or irritability that alienates family and friends just when the teenager needs them most. CBT helps teens identify these self-defeating patterns, encourages them to take part in activities they enjoy, helps develop or reactivate social skills important for maintaining positive social interactions, and helps teens to develop problem-solving strategies for resolving stressful situations.

CBT also aims to correct maladaptive beliefs associated with the patient’s depression. If, for instance, a patient believes she is worthless if she’s not accepted by the “popular” group at school, she is likely to become depressed and stay depressed as long as she is having difficulty connecting with her peers. CBT would help her examine that belief and learn to feel worthwhile even if she is not accepted by the “in” group. In general, CBT sessions are scheduled on a weekly basis for 12 to 16 weeks. In each session, the therapist and patient complete specific tasks and exercises that are provided in a CBT manual. There are also tasks for the patient to complete between sessions and review later with the therapist. CBT has been used in primary care with preliminary positive results.^13,14 However, the results of a recent RCT conducted in psychiatric settings demonstrated superior efficacy of combination therapy (fluoxetine and CBT) vs CBT alone.¹⁵

IPT for adolescents (IPT-A) is like CBT in that it is time-limited and clinicians are guided by a manual.¹⁶ A course of therapy can last anywhere from 12 to 16 sessions with optional maintenance treatment. The theoretical basis for IPT-A is the observed negative impact of depressive symptoms on interpersonal relationships, and the effect poor relationships have in causing and perpetuating depression. In deciding whether a patient may be suitable for IPT-A, you need to find out whether she would be willing to share her experiences of ongoing relationship conflicts with a therapist or therapeutic group. The relationship difficulties IPT-A is designed to help with arise from 1 of 4 sources: grief, fights with peers or family members (interpersonal disputes), transitions from one social surround to another (role transition), and friendlessness (interpersonal deficits).

IPT-A focuses on grief only when someone of significance to the patient has died. Therapy for teens who quarrel frequently with peers or family members is focused on interpersonal disputes, and this is the most common focus in IPT-A. A focus on role transition is called for when the teen’s social world has undergone a drastic change, such as a when a teen has moved to a new school or broken up with a boyfriend. Finally, therapy for a teen with no significant relationships outside the immediate family focuses on interpersonal deficits. In these cases, the goal of therapy is to increase social contact and help the patient build relationships. If your preliminary assessment identifies your patient’s difficulties as rooted in 1 of these 4 areas, IPT-A may be for her.

Because few family physicians are trained in CBT or IPT-A, most psychotherapy will be provided by mental health professionals. What you can provide is familiarity with available community mental health resources. To get to know the therapists in your community, you may want to reach out to a few of them and ask them the questions in TABLE 2. You may also want to share this list with parents who want to find their own therapist.

TABLE 2
6 questions to ask prospective therapists

Choose an antidepressant, monitor with care

Studies have shown that up to 42% of family physicians in the United States had recently prescribed selective serotonin reuptake inhibitors (SSRIs) for more than 1 adolescent under the age of 18.¹⁷ When the diagnosis of MDD without comorbid conditions is clear and the patient and family are amenable, you may want to prescribe an SSRI.^7,8

If you do, warn the patient and family that antidepressants can sometimes have adverse effects, including a switch from depressive to manic symptoms, signs of behavioral activation including agitation, hostility or restlessness, and suicidal ideation or behavior. If the patient can tolerate the medication without significant adverse effects, you need to prescribe the effective dose for at least 6 to 8 weeks to ensure an adequate trial.⁷

TABLE 3 provides some guidance for prescribing antidepressants for adolescents with depression.⁷ Among the antidepressants, only fluoxetine has been approved by the FDA for children and adolescents with depression. Fluoxetine is also the SSRI with the strongest evidence for efficacy in the adolescent population, as demonstrated in 4 RCTs.¹⁸ Two studies involving fluoxetine for depression have also shown efficacy in children as young as age 7 (range, 7-12 years).¹⁹

Effective dosages for antidepressants are lower for adolescents than for adults. Initiate medications at a low dose and increase in recommended increments every 2 weeks if no significant adverse effects emerge. With the exception of fluoxetine, SSRI medications must be discontinued slowly to minimize the risk of discontinuation effects.

Once treatment begins, you or a member of your staff will need to stay in touch with the patient and family to review their continued adherence to the treatment plan. An FDA black-box warning recommends observing for “clinical worsening, suicidality, and unusual changes in behavior” during initial visits or “at times of dose changes, either increases or decreases.” Develop a regular, frequent monitoring schedule with input from the teen and her (or his) parents to ensure compliance.^7,20

Make sure follow-up appointments are not missed, using flags in patient records or in the clinic schedule. The duration of treatment for teens with depression is yet to be determined through clinical trials. Most guidelines suggest drug therapy be continued at the same dosage for 6 to 12 months after symptoms resolve. Guidelines for the treatment of adolescent depression can be found at www.gladpc.org.

Keeping teenagers on an antidepressant regimen can be challenging, given the side effects, the amount of time it takes before they experience an improvement, and the lengthy duration of treatment. Families that know what to expect and are getting continuing support from you and others are most likely to stay with treatment for the duration.

TABLE 3
A guide to prescribing antidepressants for adolescents

What about Jane?

As the family’s physician, your initial management began with you educating Jane and her parents about mild depressive disorder and its likely course. You set up a series of weekly visits to monitor her symptoms and provide active support. You helped Jane find a peer support group and encouraged her to get back into gymnastics. You taught Jane and her family about the importance of keeping her safe while she is depressed, and they were cooperative about safety-proofing their home and setting up a plan to handle emergencies.

Jane’s depressive symptoms gradually ebbed, and she returned to her previous level of energy and social activity. You warned her and her family about the possibility that the disorder might recur, so they would be prepared.

Correspondence
Amy Cheung, MD, 33 Russell Street, 3rd Floor Tower, Toronto, Ontario, Canada MSS 2S1; dramy.cheung@gmail.com

Last month, we introduced you to 15-year-old Jane, a teenager whose once bubbly personality had in the last few months been reduced to a mood of quiet sadness. Her responses to your questions were muted, unenthusiastic. While Jane gets to school every day and can often shake off her down mood when she’s with friends, her responses to the Kutcher Adolescent Depression scale suggest that she’s struggling. You conclude that Jane is experiencing an episode of mild depressive disorder.

How would you manage Jane’s case? And what would you do if her symptoms worsened?

What’s the preference of patient and family?

Begin your initial management of a patient like Jane by considering the treatment preferences of the patient and her family, the severity and urgency of the case, the availability of mental health services, and your own comfort level with managing mental health disorders. A key conclusion of the GLAD-PC (GuideLines for Adolescent Depression in Primary Care) collaborative, described in Part 1 of this series, was that family physicians, alone or in collaboration with mental health professionals, are competent to manage adolescent depression.¹ You may or may not choose to manage a patient like Jane yourself, but even if you refer, your initial management provides an essential bridge until the patient and her family are seen by mental health professionals.

Your initial management should include the following:

• education
• a treatment plan
• safety planning.

Step 1: Educate patient and parents

Help your patient to better understand what it means to have depression. Describe the signs and symptoms that led to the diagnosis of depression and review the natural history of the illness, including the chronic nature of the disorder and its tendency to recur. Explain, too, the impact that depression can have on different areas of functioning, such as school performance and peer relationships, and then review the treatment options. You or someone on your staff can provide this patient education initially, but it is also critical to connect the family to specific community resources for additional education, advocacy, and peer support.¹

To do this effectively, you need to establish links with mental health resources in the community, including mental health service providers, as well as patients and families who have dealt with adolescent depression and are willing to serve as resources to other teens and their families. The GLAD-PC toolkit, available at www.gladpc.org, provides patient education handouts and links to reputable Web sites, advocacy organizations, and peer support groups. Additional online resources are listed in TABLE 1.

TABLE 1
Online resources

Step 2: Work out a treatment plan

Developing a treatment plan that the patient and her parents can accept is critical. A plan that includes psychotherapy with a mental health provider, for example, won’t be acceptable to some patients and parents. They may refuse to participate, or their underlying mistrust may affect the outcome of treatment.^2,3 Other families may reject any therapeutic approach that includes psychotropic drugs.

Expectations about the benefits of treatment influence outcomes significantly, so that, too, is a topic to explore as the treatment plan is worked out.^3,4 Finally, the plan should include agreed-upon goals of treatment. For Jane, planned goals might include getting back into gymnastics or trying out for the school play.

Step 3: Plan for safety

Suicidality, including ideation, behaviors, or attempts, is common among adolescents with depression.^5,6 In studies of completed suicide, more than 50% of the victims had a diagnosis of depression.⁵ To keep your patient safe, develop an emergency communication mechanism for handling increased suicidality or acute crises. If the patient’s risk is high, as shown by a clear plan or intent, immediate hospitalization may be necessary.

If you determine that inpatient treatment is not needed, you need to be sure that adequate adult supervision and support are available; that the teenager does not have access to potentially lethal medications, knives and other sharp objects, or firearms; and that both the patient and parents understand that drugs and alcohol weaken inhibitions. You need to set up a contingency plan with the family that includes checking in with you at reasonable intervals to assure the teen’s safety.⁵

Establishing a safety plan is especially important during the period of diagnosis and initial treatment, when suicide risk is highest.⁶ Confidentiality is the norm in adolescent medicine, but a patient like Jane must understand that you will breach confidentiality if that is necessary to keep her safe from harm.

Treatment options: When active support is best

Selecting the appropriate treatment modality for your patient hinges, of course, on the severity of the teen’s depression. (For more information on how to determine the severity of a depressive episode, see the first installment of this series, “Adolescent depression: Is your young patient suffering in silence?” J Fam Pract. 2009;58:187-192.)

When caring for a patient like Jane who is suffering from mild depression, consider providing active support and monitoring during 6 to 8 weekly or biweekly visits before recommending antidepressant medication or psychotherapy. This approach is also indicated when depressed patients or their parents refuse other treatments.⁷

Active support and monitoring may include education, frequent follow-up, a prescribed regimen of exercise and leisure activities, referral to a peer support group, and review of self-management goals. Other resources for active monitoring can be found in the GLAD-PC toolkit (available at www.gladpc.org). Evidence from randomized controlled trials (RCTs) shows that a sizable percentage of young people with depression respond to nondirective supportive therapy and regular symptom monitoring.⁷ Furthermore, emerging data from the research literature, expert opinion, and patient and family preferences indicate that active support and monitoring from family physicians is an important therapeutic strategy.^7,8

Is therapy needed—and if so, what kind?

Adolescents with moderate or severe depression or patients with mild depression whose symptoms do not improve with active support and monitoring alone will likely require treatment with one of the evidenced-based treatments, such as psychotherapy or antidepressants. Referral to a mental health provider for further assessment or treatment may also be required, depending on the training of the physician.^7,8 If so, you and the mental health provider will need to negotiate your roles and responsibilities for ongoing management, with the input and approval of the patient and family.

Both cognitive behavioral therapy (CBT) and interpersonal therapy (IPT) have been adapted to address major depressive disorder (MDD) in adolescents and have been shown to be effective in community as well as specialized settings.^9-11

CBT is time-limited and delivered individually or by 1 or 2 clinicians working with a group. Clinicians follow a manual to guide each session.¹² (A manual for therapists and a workbook for adolescents and parents can be downloaded from the Kaiser Permanente Center for Health Research Web site at http://www.kpchr.org/public/acwd/acwd.html.)

The focus of CBT is to change patients’ perception of themselves, their world, and others. CBT treats depression by identifying behavioral and cognitive patterns associated with depressive cycles. Examples of such patterns include the propensity to withdraw from pleasurable activities, or irritability that alienates family and friends just when the teenager needs them most. CBT helps teens identify these self-defeating patterns, encourages them to take part in activities they enjoy, helps develop or reactivate social skills important for maintaining positive social interactions, and helps teens to develop problem-solving strategies for resolving stressful situations.

CBT also aims to correct maladaptive beliefs associated with the patient’s depression. If, for instance, a patient believes she is worthless if she’s not accepted by the “popular” group at school, she is likely to become depressed and stay depressed as long as she is having difficulty connecting with her peers. CBT would help her examine that belief and learn to feel worthwhile even if she is not accepted by the “in” group. In general, CBT sessions are scheduled on a weekly basis for 12 to 16 weeks. In each session, the therapist and patient complete specific tasks and exercises that are provided in a CBT manual. There are also tasks for the patient to complete between sessions and review later with the therapist. CBT has been used in primary care with preliminary positive results.^13,14 However, the results of a recent RCT conducted in psychiatric settings demonstrated superior efficacy of combination therapy (fluoxetine and CBT) vs CBT alone.¹⁵

IPT for adolescents (IPT-A) is like CBT in that it is time-limited and clinicians are guided by a manual.¹⁶ A course of therapy can last anywhere from 12 to 16 sessions with optional maintenance treatment. The theoretical basis for IPT-A is the observed negative impact of depressive symptoms on interpersonal relationships, and the effect poor relationships have in causing and perpetuating depression. In deciding whether a patient may be suitable for IPT-A, you need to find out whether she would be willing to share her experiences of ongoing relationship conflicts with a therapist or therapeutic group. The relationship difficulties IPT-A is designed to help with arise from 1 of 4 sources: grief, fights with peers or family members (interpersonal disputes), transitions from one social surround to another (role transition), and friendlessness (interpersonal deficits).

IPT-A focuses on grief only when someone of significance to the patient has died. Therapy for teens who quarrel frequently with peers or family members is focused on interpersonal disputes, and this is the most common focus in IPT-A. A focus on role transition is called for when the teen’s social world has undergone a drastic change, such as a when a teen has moved to a new school or broken up with a boyfriend. Finally, therapy for a teen with no significant relationships outside the immediate family focuses on interpersonal deficits. In these cases, the goal of therapy is to increase social contact and help the patient build relationships. If your preliminary assessment identifies your patient’s difficulties as rooted in 1 of these 4 areas, IPT-A may be for her.

Because few family physicians are trained in CBT or IPT-A, most psychotherapy will be provided by mental health professionals. What you can provide is familiarity with available community mental health resources. To get to know the therapists in your community, you may want to reach out to a few of them and ask them the questions in TABLE 2. You may also want to share this list with parents who want to find their own therapist.

TABLE 2
6 questions to ask prospective therapists

Choose an antidepressant, monitor with care

Studies have shown that up to 42% of family physicians in the United States had recently prescribed selective serotonin reuptake inhibitors (SSRIs) for more than 1 adolescent under the age of 18.¹⁷ When the diagnosis of MDD without comorbid conditions is clear and the patient and family are amenable, you may want to prescribe an SSRI.^7,8

If you do, warn the patient and family that antidepressants can sometimes have adverse effects, including a switch from depressive to manic symptoms, signs of behavioral activation including agitation, hostility or restlessness, and suicidal ideation or behavior. If the patient can tolerate the medication without significant adverse effects, you need to prescribe the effective dose for at least 6 to 8 weeks to ensure an adequate trial.⁷

TABLE 3 provides some guidance for prescribing antidepressants for adolescents with depression.⁷ Among the antidepressants, only fluoxetine has been approved by the FDA for children and adolescents with depression. Fluoxetine is also the SSRI with the strongest evidence for efficacy in the adolescent population, as demonstrated in 4 RCTs.¹⁸ Two studies involving fluoxetine for depression have also shown efficacy in children as young as age 7 (range, 7-12 years).¹⁹

Effective dosages for antidepressants are lower for adolescents than for adults. Initiate medications at a low dose and increase in recommended increments every 2 weeks if no significant adverse effects emerge. With the exception of fluoxetine, SSRI medications must be discontinued slowly to minimize the risk of discontinuation effects.

Once treatment begins, you or a member of your staff will need to stay in touch with the patient and family to review their continued adherence to the treatment plan. An FDA black-box warning recommends observing for “clinical worsening, suicidality, and unusual changes in behavior” during initial visits or “at times of dose changes, either increases or decreases.” Develop a regular, frequent monitoring schedule with input from the teen and her (or his) parents to ensure compliance.^7,20

Make sure follow-up appointments are not missed, using flags in patient records or in the clinic schedule. The duration of treatment for teens with depression is yet to be determined through clinical trials. Most guidelines suggest drug therapy be continued at the same dosage for 6 to 12 months after symptoms resolve. Guidelines for the treatment of adolescent depression can be found at www.gladpc.org.

Keeping teenagers on an antidepressant regimen can be challenging, given the side effects, the amount of time it takes before they experience an improvement, and the lengthy duration of treatment. Families that know what to expect and are getting continuing support from you and others are most likely to stay with treatment for the duration.

TABLE 3
A guide to prescribing antidepressants for adolescents

What about Jane?

As the family’s physician, your initial management began with you educating Jane and her parents about mild depressive disorder and its likely course. You set up a series of weekly visits to monitor her symptoms and provide active support. You helped Jane find a peer support group and encouraged her to get back into gymnastics. You taught Jane and her family about the importance of keeping her safe while she is depressed, and they were cooperative about safety-proofing their home and setting up a plan to handle emergencies.

Jane’s depressive symptoms gradually ebbed, and she returned to her previous level of energy and social activity. You warned her and her family about the possibility that the disorder might recur, so they would be prepared.

Correspondence
Amy Cheung, MD, 33 Russell Street, 3rd Floor Tower, Toronto, Ontario, Canada MSS 2S1; dramy.cheung@gmail.com

Last month, we introduced you to 15-year-old Jane, a teenager whose once bubbly personality had in the last few months been reduced to a mood of quiet sadness. Her responses to your questions were muted, unenthusiastic. While Jane gets to school every day and can often shake off her down mood when she’s with friends, her responses to the Kutcher Adolescent Depression scale suggest that she’s struggling. You conclude that Jane is experiencing an episode of mild depressive disorder.

How would you manage Jane’s case? And what would you do if her symptoms worsened?

What’s the preference of patient and family?

Begin your initial management of a patient like Jane by considering the treatment preferences of the patient and her family, the severity and urgency of the case, the availability of mental health services, and your own comfort level with managing mental health disorders. A key conclusion of the GLAD-PC (GuideLines for Adolescent Depression in Primary Care) collaborative, described in Part 1 of this series, was that family physicians, alone or in collaboration with mental health professionals, are competent to manage adolescent depression.¹ You may or may not choose to manage a patient like Jane yourself, but even if you refer, your initial management provides an essential bridge until the patient and her family are seen by mental health professionals.

Your initial management should include the following:

• education
• a treatment plan
• safety planning.

Step 1: Educate patient and parents

Help your patient to better understand what it means to have depression. Describe the signs and symptoms that led to the diagnosis of depression and review the natural history of the illness, including the chronic nature of the disorder and its tendency to recur. Explain, too, the impact that depression can have on different areas of functioning, such as school performance and peer relationships, and then review the treatment options. You or someone on your staff can provide this patient education initially, but it is also critical to connect the family to specific community resources for additional education, advocacy, and peer support.¹

To do this effectively, you need to establish links with mental health resources in the community, including mental health service providers, as well as patients and families who have dealt with adolescent depression and are willing to serve as resources to other teens and their families. The GLAD-PC toolkit, available at www.gladpc.org, provides patient education handouts and links to reputable Web sites, advocacy organizations, and peer support groups. Additional online resources are listed in TABLE 1.

TABLE 1
Online resources

Step 2: Work out a treatment plan

Developing a treatment plan that the patient and her parents can accept is critical. A plan that includes psychotherapy with a mental health provider, for example, won’t be acceptable to some patients and parents. They may refuse to participate, or their underlying mistrust may affect the outcome of treatment.^2,3 Other families may reject any therapeutic approach that includes psychotropic drugs.

Expectations about the benefits of treatment influence outcomes significantly, so that, too, is a topic to explore as the treatment plan is worked out.^3,4 Finally, the plan should include agreed-upon goals of treatment. For Jane, planned goals might include getting back into gymnastics or trying out for the school play.

Step 3: Plan for safety

Suicidality, including ideation, behaviors, or attempts, is common among adolescents with depression.^5,6 In studies of completed suicide, more than 50% of the victims had a diagnosis of depression.⁵ To keep your patient safe, develop an emergency communication mechanism for handling increased suicidality or acute crises. If the patient’s risk is high, as shown by a clear plan or intent, immediate hospitalization may be necessary.

If you determine that inpatient treatment is not needed, you need to be sure that adequate adult supervision and support are available; that the teenager does not have access to potentially lethal medications, knives and other sharp objects, or firearms; and that both the patient and parents understand that drugs and alcohol weaken inhibitions. You need to set up a contingency plan with the family that includes checking in with you at reasonable intervals to assure the teen’s safety.⁵

Establishing a safety plan is especially important during the period of diagnosis and initial treatment, when suicide risk is highest.⁶ Confidentiality is the norm in adolescent medicine, but a patient like Jane must understand that you will breach confidentiality if that is necessary to keep her safe from harm.

Treatment options: When active support is best

Selecting the appropriate treatment modality for your patient hinges, of course, on the severity of the teen’s depression. (For more information on how to determine the severity of a depressive episode, see the first installment of this series, “Adolescent depression: Is your young patient suffering in silence?” J Fam Pract. 2009;58:187-192.)

When caring for a patient like Jane who is suffering from mild depression, consider providing active support and monitoring during 6 to 8 weekly or biweekly visits before recommending antidepressant medication or psychotherapy. This approach is also indicated when depressed patients or their parents refuse other treatments.⁷

Active support and monitoring may include education, frequent follow-up, a prescribed regimen of exercise and leisure activities, referral to a peer support group, and review of self-management goals. Other resources for active monitoring can be found in the GLAD-PC toolkit (available at www.gladpc.org). Evidence from randomized controlled trials (RCTs) shows that a sizable percentage of young people with depression respond to nondirective supportive therapy and regular symptom monitoring.⁷ Furthermore, emerging data from the research literature, expert opinion, and patient and family preferences indicate that active support and monitoring from family physicians is an important therapeutic strategy.^7,8

Is therapy needed—and if so, what kind?

Adolescents with moderate or severe depression or patients with mild depression whose symptoms do not improve with active support and monitoring alone will likely require treatment with one of the evidenced-based treatments, such as psychotherapy or antidepressants. Referral to a mental health provider for further assessment or treatment may also be required, depending on the training of the physician.^7,8 If so, you and the mental health provider will need to negotiate your roles and responsibilities for ongoing management, with the input and approval of the patient and family.

Both cognitive behavioral therapy (CBT) and interpersonal therapy (IPT) have been adapted to address major depressive disorder (MDD) in adolescents and have been shown to be effective in community as well as specialized settings.^9-11

CBT is time-limited and delivered individually or by 1 or 2 clinicians working with a group. Clinicians follow a manual to guide each session.¹² (A manual for therapists and a workbook for adolescents and parents can be downloaded from the Kaiser Permanente Center for Health Research Web site at http://www.kpchr.org/public/acwd/acwd.html.)

The focus of CBT is to change patients’ perception of themselves, their world, and others. CBT treats depression by identifying behavioral and cognitive patterns associated with depressive cycles. Examples of such patterns include the propensity to withdraw from pleasurable activities, or irritability that alienates family and friends just when the teenager needs them most. CBT helps teens identify these self-defeating patterns, encourages them to take part in activities they enjoy, helps develop or reactivate social skills important for maintaining positive social interactions, and helps teens to develop problem-solving strategies for resolving stressful situations.

CBT also aims to correct maladaptive beliefs associated with the patient’s depression. If, for instance, a patient believes she is worthless if she’s not accepted by the “popular” group at school, she is likely to become depressed and stay depressed as long as she is having difficulty connecting with her peers. CBT would help her examine that belief and learn to feel worthwhile even if she is not accepted by the “in” group. In general, CBT sessions are scheduled on a weekly basis for 12 to 16 weeks. In each session, the therapist and patient complete specific tasks and exercises that are provided in a CBT manual. There are also tasks for the patient to complete between sessions and review later with the therapist. CBT has been used in primary care with preliminary positive results.^13,14 However, the results of a recent RCT conducted in psychiatric settings demonstrated superior efficacy of combination therapy (fluoxetine and CBT) vs CBT alone.¹⁵

IPT for adolescents (IPT-A) is like CBT in that it is time-limited and clinicians are guided by a manual.¹⁶ A course of therapy can last anywhere from 12 to 16 sessions with optional maintenance treatment. The theoretical basis for IPT-A is the observed negative impact of depressive symptoms on interpersonal relationships, and the effect poor relationships have in causing and perpetuating depression. In deciding whether a patient may be suitable for IPT-A, you need to find out whether she would be willing to share her experiences of ongoing relationship conflicts with a therapist or therapeutic group. The relationship difficulties IPT-A is designed to help with arise from 1 of 4 sources: grief, fights with peers or family members (interpersonal disputes), transitions from one social surround to another (role transition), and friendlessness (interpersonal deficits).

IPT-A focuses on grief only when someone of significance to the patient has died. Therapy for teens who quarrel frequently with peers or family members is focused on interpersonal disputes, and this is the most common focus in IPT-A. A focus on role transition is called for when the teen’s social world has undergone a drastic change, such as a when a teen has moved to a new school or broken up with a boyfriend. Finally, therapy for a teen with no significant relationships outside the immediate family focuses on interpersonal deficits. In these cases, the goal of therapy is to increase social contact and help the patient build relationships. If your preliminary assessment identifies your patient’s difficulties as rooted in 1 of these 4 areas, IPT-A may be for her.

Because few family physicians are trained in CBT or IPT-A, most psychotherapy will be provided by mental health professionals. What you can provide is familiarity with available community mental health resources. To get to know the therapists in your community, you may want to reach out to a few of them and ask them the questions in TABLE 2. You may also want to share this list with parents who want to find their own therapist.

TABLE 2
6 questions to ask prospective therapists

Choose an antidepressant, monitor with care

Studies have shown that up to 42% of family physicians in the United States had recently prescribed selective serotonin reuptake inhibitors (SSRIs) for more than 1 adolescent under the age of 18.¹⁷ When the diagnosis of MDD without comorbid conditions is clear and the patient and family are amenable, you may want to prescribe an SSRI.^7,8

If you do, warn the patient and family that antidepressants can sometimes have adverse effects, including a switch from depressive to manic symptoms, signs of behavioral activation including agitation, hostility or restlessness, and suicidal ideation or behavior. If the patient can tolerate the medication without significant adverse effects, you need to prescribe the effective dose for at least 6 to 8 weeks to ensure an adequate trial.⁷

TABLE 3 provides some guidance for prescribing antidepressants for adolescents with depression.⁷ Among the antidepressants, only fluoxetine has been approved by the FDA for children and adolescents with depression. Fluoxetine is also the SSRI with the strongest evidence for efficacy in the adolescent population, as demonstrated in 4 RCTs.¹⁸ Two studies involving fluoxetine for depression have also shown efficacy in children as young as age 7 (range, 7-12 years).¹⁹

Effective dosages for antidepressants are lower for adolescents than for adults. Initiate medications at a low dose and increase in recommended increments every 2 weeks if no significant adverse effects emerge. With the exception of fluoxetine, SSRI medications must be discontinued slowly to minimize the risk of discontinuation effects.

Once treatment begins, you or a member of your staff will need to stay in touch with the patient and family to review their continued adherence to the treatment plan. An FDA black-box warning recommends observing for “clinical worsening, suicidality, and unusual changes in behavior” during initial visits or “at times of dose changes, either increases or decreases.” Develop a regular, frequent monitoring schedule with input from the teen and her (or his) parents to ensure compliance.^7,20

Make sure follow-up appointments are not missed, using flags in patient records or in the clinic schedule. The duration of treatment for teens with depression is yet to be determined through clinical trials. Most guidelines suggest drug therapy be continued at the same dosage for 6 to 12 months after symptoms resolve. Guidelines for the treatment of adolescent depression can be found at www.gladpc.org.

Keeping teenagers on an antidepressant regimen can be challenging, given the side effects, the amount of time it takes before they experience an improvement, and the lengthy duration of treatment. Families that know what to expect and are getting continuing support from you and others are most likely to stay with treatment for the duration.

TABLE 3
A guide to prescribing antidepressants for adolescents

What about Jane?

As the family’s physician, your initial management began with you educating Jane and her parents about mild depressive disorder and its likely course. You set up a series of weekly visits to monitor her symptoms and provide active support. You helped Jane find a peer support group and encouraged her to get back into gymnastics. You taught Jane and her family about the importance of keeping her safe while she is depressed, and they were cooperative about safety-proofing their home and setting up a plan to handle emergencies.

Jane’s depressive symptoms gradually ebbed, and she returned to her previous level of energy and social activity. You warned her and her family about the possibility that the disorder might recur, so they would be prepared.

Correspondence
Amy Cheung, MD, 33 Russell Street, 3rd Floor Tower, Toronto, Ontario, Canada MSS 2S1; dramy.cheung@gmail.com

ILLUSTRATIVE CASE

Case 1: A healthy 25-year-old woman comes to see you because she’s worried about getting pregnant. She’s been on an extended-cycle oral contraceptive (OC) for several months and is happy to have her period only once every 3 months, but she frequently forgets to take her pill.

What can you offer that will give her the benefits of an extended-cycle OC, without the risk of pregnancy she incurs each time she misses a pill?

Case 2: You started a healthy 18-year-old on the transvaginal ring 6 months ago. After counseling, she opted for continuous cycling, so she inserts a new ring right after she removes the old one, on the same date each month. Although she likes the ring, she’s disturbed by a recent increase in breakthrough bleeding. What can you recommend to decrease the bleeding?

Clinicians have long known that the traditional 21/7 OC cycle is not necessary for safety or efficacy. More recently, many women have been happy to learn that there is no physiologic reason to have a monthly period when they’re using combination hormonal contraception. They’re also happy to discover that fewer periods often mean fewer premenstrual mood swings, episodes of painful cramping, and instances of other troublesome symptoms.

The transvaginal ring is often overlooked

The US Food and Drug Administration (FDA) has approved 2 combination OCs for extended-cycle use and 1 for continuous use. But any monophasic OC can be used off-label for extended or continuous cycling to decrease bleeding frequency. So, too, can the transvaginal contraceptive ring (NuvaRing), an infrequently used contraceptive. (According to 1 study, just 5.7% of US women using contraception used either the ring or the patch.² ) The ring has been studied for extended use,³ but does not have FDA approval for longer-term regimens.

NuvaRing is a flexible, transparent device that contains the progestin etonogestrel and ethinyl estradiol. The manufacturer recommends a 21/7 cycle, inserting the ring in the vagina and leaving it in place for 3 weeks, removing it for 1 week, and then inserting a new ring.⁴ The ring is well suited to women who have no contraindications to hormonal contraception but have difficulty remembering to take a pill every day—or simply prefer the convenience of less frequent dosing.

While the ring has been found to be effective and tolerable when used without a hormone-free interval—28-, 49-, 91- and 364-day dosing has been studied—breakthrough bleeding or spotting is a frequent side effect of extended-cycle hormonal contraception. In 1 study, 43% of women on a 49-day ring cycle experienced breakthrough bleeding, compared with 16% of those on a 28-day cycle.³

High satisfaction, low risk

Nonetheless, women who use the transvaginal ring often report high satisfaction. One study found that 61% of women were very satisfied with this method of contraception, compared with 34% of triphasic OC users (P<.003).⁵ The risk of pregnancy (1-2 pregnancies per 100 women-years of use, according to the manufacturer⁴ ) and the risk of venous thromboembolism (10-30 in 100,000 vs 4-11 in 100,000 nonpregnant women who are not using hormonal contraception) are comparable to that of women using OCs.^6,7 The risk of other severe side effects associated with the vaginal ring is comparable to that of OCs, as well.

STUDY SUMMARY: An effective option that women used post-trial

This RCT recruited women between the ages of 18 and 45 years who had been using combination hormonal contraceptives—OCs, the transdermal patch, or the transvaginal ring. All had been on a 21/7 cycle for at least 2 months. Exclusion criteria included a body mass index ≥38 kg/m², smoking >10 cigarettes per day, use of other estrogen- or phytoestrogen-containing products, and the presence of ovarian cysts >2.5 cm or endometrial thickness >8 mm. Women who wanted to get pregnant within a year were also excluded.

The study began with a baseline phase during which participants completed one 21/7 cycle with the ring for those using the ring prior to the study or two 21/7 cycles for those using the pill or patch prior to the study. Daily flow was assessed during this initial phase, using a scale of 0 to 4, with 4 being the heaviest. Women who completed this phase and wanted to continue using the ring (N=74) were then randomized into 2 groups (n=37) for the 6-month extended phase.

Group 1 was assigned to use the contraceptive ring with no hormone-free days. Participants were instructed to replace the rings monthly, on the same calendar day of the month. Group 2 also used the ring on a continuous basis with monthly replacement, but those who experienced breakthrough bleeding for more than 5 days were permitted to remove the ring for 4 days. Women in both groups kept a daily diary of ring usage, degree of menstrual flow, and symptomatology, including pelvic pain, headaches, and mood.

Most subjects were white (76%), nonsmokers (84%), and unmarried (68% in Group 1 and 57% in Group 2), with an average age of 28 to 29 years. Eight patients (22%) in Group 1 withdrew from the study prior to completing the 6-month extended phase, 4 of them because of side effects. Only 1 woman withdrew from Group 2, because of plans for pregnancy. No one became pregnant while using the ring.

Hormone-free interval reduced bleeding. In Group 1, the average daily flow score was slightly reduced with continuous use (from 0.33 during the 21/7 baseline phase to 0.21 in the 6-month extended phase), but researchers reported no significant difference in flow-free days. On average, 85% of the days were flow-free in the 21/7 phase, vs 89% in the extended phase.

In Group 2, flow-free days increased, from 83% in the baseline phase to 95% in the extended phase, and average flow scores fell from 0.38 to 0.17.

Overall, the 65 participants who completed 6 months of continuous ring use had fewer bleeding days per month—1.8 days, on average, vs 3.3 days during the initial 21/7 phase, but more days of spotting per month (2.5 vs 1.8 days). There was no difference between Groups 1 and 2 in pelvic pain, headache, or mood scores, and no significant difference in headache or mood scores between the baseline and continuous phases of the trial. Pelvic pain scores were lower during the extended phase, however—0.18 vs 0.32 on a scale of 0 to 10.

A high continuation rate. After the 6-month extended phase, 57 of the 65 remaining participants chose to continue using the ring for contraception, on a continuous dosing basis—a continuation rate of 88%. But more than half of the women who chose to stick with the ring (57%) decided not to take advantage of the 4-day hormone-free interval to manage breakthrough bleeding or spotting, regardless of original group assignment.

WHAT’S NEW?: The ring moves further mainstream

Continuous or extended use of the transvaginal ring may be a new idea for many patients—and physicians. But the idea may catch on in light of this study’s findings. Given the high rate of unwanted pregnancy in the United States, many women may benefit from a contraceptive that is as safe and effective as an OC but doesn’t involve a daily pill.

CAVEATS: Side effects, off-label concerns

In 2005, Oddsson et al found that women who used the ring reported more vaginitis and more leukorrhea than women who used OCs; conversely, they reported less nausea and less acne. Other side effects that are common to hormonal contraceptives, such as headache and weight gain, occurred at similar rates among women using the ring and OCs.⁶

However, the high proportion of patients who elected to keep using the ring at the end of the study by Sulak et al suggests that its side effects are acceptable.¹ As with all contraception, however, patient preference is a key consideration. The study population was highly motivated, particularly since women who had difficulty with this means of contraception dropped out after the baseline phase of the trial.

Off-label use. Pharmacokinetic research involving the contraceptive ring has shown that hormone levels required to protect against pregnancy persist for at least 35 days after it is placed in the vagina.⁸ The manufacturer has data only to confirm contraceptive efficacy for up to 28 days and therefore does not recommend use beyond 4 weeks.⁴

This study highlights another off-label issue: Women in Group 2, who were allowed to remove the ring for 4 day-intervals to decrease breakthrough bleeding, were instructed to reinsert the same ring after 4 days and keep it in place until the next scheduled replacement date. But the manufacturer does not recommend reinsertion of a ring that has been out of the body for more than 3 hours. In my practice (KR), women are generally unwilling to store and replace a ring, preferring to place a new one after removal for more than a few hours.

Should she try continuous use?

Changing the ring on the same date each month may boost adherence for some women. Funding. The research was funded by an unrestricted educational grant from Organon, Inc, the manufacturer of NuvaRing, which included salary support for 5 of the 6 authors. The published study gives no additional information about the involvement of the pharmaceutical company.

Contraindications, drug interactions. As with other combined hormonal contraceptives, women who have a history of venous thromboembolism, headaches with focal neurological symptoms, severe hypertension, breast or endometrial cancer, or liver disease, and smokers older than 35 years should not use the contraceptive ring.⁴ In addition, women need to be aware that a number of medications—griseofulvin, rifampin, phenytoin, carbamazepine, and herbal products containing St. John’s Wort, among others—may reduce the effectiveness of the contraceptive ring.⁴

CHALLENGES TO IMPLEMENTATION: Going off-label isn’t for everyone

When it comes to choosing a contraceptive method, patient preference is paramount. Some women may not be comfortable inserting or removing the ring and should be counseled on other forms of contraception. Women who prefer to bleed every month should not use extended cycling. Similarly, some physicians may not be comfortable recommending an off-label use of the ring.

Those who are comfortable making the recommendation should be prepared to educate patients about this method of contraception and to discuss the benefits of extended or continuous use of the ring. For some women, the memory-triggering mechanism of changing the ring on the same date each month may boost adherence. For others, replacing the ring every 28 days may be acceptable—again, depending on patient preference.

Acknowledgements

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

PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURLs) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

Case 1: A healthy 25-year-old woman comes to see you because she’s worried about getting pregnant. She’s been on an extended-cycle oral contraceptive (OC) for several months and is happy to have her period only once every 3 months, but she frequently forgets to take her pill.

What can you offer that will give her the benefits of an extended-cycle OC, without the risk of pregnancy she incurs each time she misses a pill?

Case 2: You started a healthy 18-year-old on the transvaginal ring 6 months ago. After counseling, she opted for continuous cycling, so she inserts a new ring right after she removes the old one, on the same date each month. Although she likes the ring, she’s disturbed by a recent increase in breakthrough bleeding. What can you recommend to decrease the bleeding?

Clinicians have long known that the traditional 21/7 OC cycle is not necessary for safety or efficacy. More recently, many women have been happy to learn that there is no physiologic reason to have a monthly period when they’re using combination hormonal contraception. They’re also happy to discover that fewer periods often mean fewer premenstrual mood swings, episodes of painful cramping, and instances of other troublesome symptoms.

The transvaginal ring is often overlooked

The US Food and Drug Administration (FDA) has approved 2 combination OCs for extended-cycle use and 1 for continuous use. But any monophasic OC can be used off-label for extended or continuous cycling to decrease bleeding frequency. So, too, can the transvaginal contraceptive ring (NuvaRing), an infrequently used contraceptive. (According to 1 study, just 5.7% of US women using contraception used either the ring or the patch.² ) The ring has been studied for extended use,³ but does not have FDA approval for longer-term regimens.

NuvaRing is a flexible, transparent device that contains the progestin etonogestrel and ethinyl estradiol. The manufacturer recommends a 21/7 cycle, inserting the ring in the vagina and leaving it in place for 3 weeks, removing it for 1 week, and then inserting a new ring.⁴ The ring is well suited to women who have no contraindications to hormonal contraception but have difficulty remembering to take a pill every day—or simply prefer the convenience of less frequent dosing.

While the ring has been found to be effective and tolerable when used without a hormone-free interval—28-, 49-, 91- and 364-day dosing has been studied—breakthrough bleeding or spotting is a frequent side effect of extended-cycle hormonal contraception. In 1 study, 43% of women on a 49-day ring cycle experienced breakthrough bleeding, compared with 16% of those on a 28-day cycle.³

High satisfaction, low risk

Nonetheless, women who use the transvaginal ring often report high satisfaction. One study found that 61% of women were very satisfied with this method of contraception, compared with 34% of triphasic OC users (P<.003).⁵ The risk of pregnancy (1-2 pregnancies per 100 women-years of use, according to the manufacturer⁴ ) and the risk of venous thromboembolism (10-30 in 100,000 vs 4-11 in 100,000 nonpregnant women who are not using hormonal contraception) are comparable to that of women using OCs.^6,7 The risk of other severe side effects associated with the vaginal ring is comparable to that of OCs, as well.

STUDY SUMMARY: An effective option that women used post-trial

This RCT recruited women between the ages of 18 and 45 years who had been using combination hormonal contraceptives—OCs, the transdermal patch, or the transvaginal ring. All had been on a 21/7 cycle for at least 2 months. Exclusion criteria included a body mass index ≥38 kg/m², smoking >10 cigarettes per day, use of other estrogen- or phytoestrogen-containing products, and the presence of ovarian cysts >2.5 cm or endometrial thickness >8 mm. Women who wanted to get pregnant within a year were also excluded.

The study began with a baseline phase during which participants completed one 21/7 cycle with the ring for those using the ring prior to the study or two 21/7 cycles for those using the pill or patch prior to the study. Daily flow was assessed during this initial phase, using a scale of 0 to 4, with 4 being the heaviest. Women who completed this phase and wanted to continue using the ring (N=74) were then randomized into 2 groups (n=37) for the 6-month extended phase.

Group 1 was assigned to use the contraceptive ring with no hormone-free days. Participants were instructed to replace the rings monthly, on the same calendar day of the month. Group 2 also used the ring on a continuous basis with monthly replacement, but those who experienced breakthrough bleeding for more than 5 days were permitted to remove the ring for 4 days. Women in both groups kept a daily diary of ring usage, degree of menstrual flow, and symptomatology, including pelvic pain, headaches, and mood.

Most subjects were white (76%), nonsmokers (84%), and unmarried (68% in Group 1 and 57% in Group 2), with an average age of 28 to 29 years. Eight patients (22%) in Group 1 withdrew from the study prior to completing the 6-month extended phase, 4 of them because of side effects. Only 1 woman withdrew from Group 2, because of plans for pregnancy. No one became pregnant while using the ring.

Hormone-free interval reduced bleeding. In Group 1, the average daily flow score was slightly reduced with continuous use (from 0.33 during the 21/7 baseline phase to 0.21 in the 6-month extended phase), but researchers reported no significant difference in flow-free days. On average, 85% of the days were flow-free in the 21/7 phase, vs 89% in the extended phase.

In Group 2, flow-free days increased, from 83% in the baseline phase to 95% in the extended phase, and average flow scores fell from 0.38 to 0.17.

Overall, the 65 participants who completed 6 months of continuous ring use had fewer bleeding days per month—1.8 days, on average, vs 3.3 days during the initial 21/7 phase, but more days of spotting per month (2.5 vs 1.8 days). There was no difference between Groups 1 and 2 in pelvic pain, headache, or mood scores, and no significant difference in headache or mood scores between the baseline and continuous phases of the trial. Pelvic pain scores were lower during the extended phase, however—0.18 vs 0.32 on a scale of 0 to 10.

A high continuation rate. After the 6-month extended phase, 57 of the 65 remaining participants chose to continue using the ring for contraception, on a continuous dosing basis—a continuation rate of 88%. But more than half of the women who chose to stick with the ring (57%) decided not to take advantage of the 4-day hormone-free interval to manage breakthrough bleeding or spotting, regardless of original group assignment.

WHAT’S NEW?: The ring moves further mainstream

Continuous or extended use of the transvaginal ring may be a new idea for many patients—and physicians. But the idea may catch on in light of this study’s findings. Given the high rate of unwanted pregnancy in the United States, many women may benefit from a contraceptive that is as safe and effective as an OC but doesn’t involve a daily pill.

CAVEATS: Side effects, off-label concerns

In 2005, Oddsson et al found that women who used the ring reported more vaginitis and more leukorrhea than women who used OCs; conversely, they reported less nausea and less acne. Other side effects that are common to hormonal contraceptives, such as headache and weight gain, occurred at similar rates among women using the ring and OCs.⁶

However, the high proportion of patients who elected to keep using the ring at the end of the study by Sulak et al suggests that its side effects are acceptable.¹ As with all contraception, however, patient preference is a key consideration. The study population was highly motivated, particularly since women who had difficulty with this means of contraception dropped out after the baseline phase of the trial.

Off-label use. Pharmacokinetic research involving the contraceptive ring has shown that hormone levels required to protect against pregnancy persist for at least 35 days after it is placed in the vagina.⁸ The manufacturer has data only to confirm contraceptive efficacy for up to 28 days and therefore does not recommend use beyond 4 weeks.⁴

This study highlights another off-label issue: Women in Group 2, who were allowed to remove the ring for 4 day-intervals to decrease breakthrough bleeding, were instructed to reinsert the same ring after 4 days and keep it in place until the next scheduled replacement date. But the manufacturer does not recommend reinsertion of a ring that has been out of the body for more than 3 hours. In my practice (KR), women are generally unwilling to store and replace a ring, preferring to place a new one after removal for more than a few hours.

Should she try continuous use?

Changing the ring on the same date each month may boost adherence for some women. Funding. The research was funded by an unrestricted educational grant from Organon, Inc, the manufacturer of NuvaRing, which included salary support for 5 of the 6 authors. The published study gives no additional information about the involvement of the pharmaceutical company.

Contraindications, drug interactions. As with other combined hormonal contraceptives, women who have a history of venous thromboembolism, headaches with focal neurological symptoms, severe hypertension, breast or endometrial cancer, or liver disease, and smokers older than 35 years should not use the contraceptive ring.⁴ In addition, women need to be aware that a number of medications—griseofulvin, rifampin, phenytoin, carbamazepine, and herbal products containing St. John’s Wort, among others—may reduce the effectiveness of the contraceptive ring.⁴

CHALLENGES TO IMPLEMENTATION: Going off-label isn’t for everyone

When it comes to choosing a contraceptive method, patient preference is paramount. Some women may not be comfortable inserting or removing the ring and should be counseled on other forms of contraception. Women who prefer to bleed every month should not use extended cycling. Similarly, some physicians may not be comfortable recommending an off-label use of the ring.

Those who are comfortable making the recommendation should be prepared to educate patients about this method of contraception and to discuss the benefits of extended or continuous use of the ring. For some women, the memory-triggering mechanism of changing the ring on the same date each month may boost adherence. For others, replacing the ring every 28 days may be acceptable—again, depending on patient preference.

Acknowledgements

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

PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURLs) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

Case 1: A healthy 25-year-old woman comes to see you because she’s worried about getting pregnant. She’s been on an extended-cycle oral contraceptive (OC) for several months and is happy to have her period only once every 3 months, but she frequently forgets to take her pill.

What can you offer that will give her the benefits of an extended-cycle OC, without the risk of pregnancy she incurs each time she misses a pill?

Case 2: You started a healthy 18-year-old on the transvaginal ring 6 months ago. After counseling, she opted for continuous cycling, so she inserts a new ring right after she removes the old one, on the same date each month. Although she likes the ring, she’s disturbed by a recent increase in breakthrough bleeding. What can you recommend to decrease the bleeding?

Clinicians have long known that the traditional 21/7 OC cycle is not necessary for safety or efficacy. More recently, many women have been happy to learn that there is no physiologic reason to have a monthly period when they’re using combination hormonal contraception. They’re also happy to discover that fewer periods often mean fewer premenstrual mood swings, episodes of painful cramping, and instances of other troublesome symptoms.

The transvaginal ring is often overlooked

The US Food and Drug Administration (FDA) has approved 2 combination OCs for extended-cycle use and 1 for continuous use. But any monophasic OC can be used off-label for extended or continuous cycling to decrease bleeding frequency. So, too, can the transvaginal contraceptive ring (NuvaRing), an infrequently used contraceptive. (According to 1 study, just 5.7% of US women using contraception used either the ring or the patch.² ) The ring has been studied for extended use,³ but does not have FDA approval for longer-term regimens.

NuvaRing is a flexible, transparent device that contains the progestin etonogestrel and ethinyl estradiol. The manufacturer recommends a 21/7 cycle, inserting the ring in the vagina and leaving it in place for 3 weeks, removing it for 1 week, and then inserting a new ring.⁴ The ring is well suited to women who have no contraindications to hormonal contraception but have difficulty remembering to take a pill every day—or simply prefer the convenience of less frequent dosing.

While the ring has been found to be effective and tolerable when used without a hormone-free interval—28-, 49-, 91- and 364-day dosing has been studied—breakthrough bleeding or spotting is a frequent side effect of extended-cycle hormonal contraception. In 1 study, 43% of women on a 49-day ring cycle experienced breakthrough bleeding, compared with 16% of those on a 28-day cycle.³

High satisfaction, low risk

Nonetheless, women who use the transvaginal ring often report high satisfaction. One study found that 61% of women were very satisfied with this method of contraception, compared with 34% of triphasic OC users (P<.003).⁵ The risk of pregnancy (1-2 pregnancies per 100 women-years of use, according to the manufacturer⁴ ) and the risk of venous thromboembolism (10-30 in 100,000 vs 4-11 in 100,000 nonpregnant women who are not using hormonal contraception) are comparable to that of women using OCs.^6,7 The risk of other severe side effects associated with the vaginal ring is comparable to that of OCs, as well.

STUDY SUMMARY: An effective option that women used post-trial

This RCT recruited women between the ages of 18 and 45 years who had been using combination hormonal contraceptives—OCs, the transdermal patch, or the transvaginal ring. All had been on a 21/7 cycle for at least 2 months. Exclusion criteria included a body mass index ≥38 kg/m², smoking >10 cigarettes per day, use of other estrogen- or phytoestrogen-containing products, and the presence of ovarian cysts >2.5 cm or endometrial thickness >8 mm. Women who wanted to get pregnant within a year were also excluded.

The study began with a baseline phase during which participants completed one 21/7 cycle with the ring for those using the ring prior to the study or two 21/7 cycles for those using the pill or patch prior to the study. Daily flow was assessed during this initial phase, using a scale of 0 to 4, with 4 being the heaviest. Women who completed this phase and wanted to continue using the ring (N=74) were then randomized into 2 groups (n=37) for the 6-month extended phase.

Group 1 was assigned to use the contraceptive ring with no hormone-free days. Participants were instructed to replace the rings monthly, on the same calendar day of the month. Group 2 also used the ring on a continuous basis with monthly replacement, but those who experienced breakthrough bleeding for more than 5 days were permitted to remove the ring for 4 days. Women in both groups kept a daily diary of ring usage, degree of menstrual flow, and symptomatology, including pelvic pain, headaches, and mood.

Most subjects were white (76%), nonsmokers (84%), and unmarried (68% in Group 1 and 57% in Group 2), with an average age of 28 to 29 years. Eight patients (22%) in Group 1 withdrew from the study prior to completing the 6-month extended phase, 4 of them because of side effects. Only 1 woman withdrew from Group 2, because of plans for pregnancy. No one became pregnant while using the ring.

Hormone-free interval reduced bleeding. In Group 1, the average daily flow score was slightly reduced with continuous use (from 0.33 during the 21/7 baseline phase to 0.21 in the 6-month extended phase), but researchers reported no significant difference in flow-free days. On average, 85% of the days were flow-free in the 21/7 phase, vs 89% in the extended phase.

In Group 2, flow-free days increased, from 83% in the baseline phase to 95% in the extended phase, and average flow scores fell from 0.38 to 0.17.

Overall, the 65 participants who completed 6 months of continuous ring use had fewer bleeding days per month—1.8 days, on average, vs 3.3 days during the initial 21/7 phase, but more days of spotting per month (2.5 vs 1.8 days). There was no difference between Groups 1 and 2 in pelvic pain, headache, or mood scores, and no significant difference in headache or mood scores between the baseline and continuous phases of the trial. Pelvic pain scores were lower during the extended phase, however—0.18 vs 0.32 on a scale of 0 to 10.

A high continuation rate. After the 6-month extended phase, 57 of the 65 remaining participants chose to continue using the ring for contraception, on a continuous dosing basis—a continuation rate of 88%. But more than half of the women who chose to stick with the ring (57%) decided not to take advantage of the 4-day hormone-free interval to manage breakthrough bleeding or spotting, regardless of original group assignment.

WHAT’S NEW?: The ring moves further mainstream

Continuous or extended use of the transvaginal ring may be a new idea for many patients—and physicians. But the idea may catch on in light of this study’s findings. Given the high rate of unwanted pregnancy in the United States, many women may benefit from a contraceptive that is as safe and effective as an OC but doesn’t involve a daily pill.

CAVEATS: Side effects, off-label concerns

In 2005, Oddsson et al found that women who used the ring reported more vaginitis and more leukorrhea than women who used OCs; conversely, they reported less nausea and less acne. Other side effects that are common to hormonal contraceptives, such as headache and weight gain, occurred at similar rates among women using the ring and OCs.⁶

However, the high proportion of patients who elected to keep using the ring at the end of the study by Sulak et al suggests that its side effects are acceptable.¹ As with all contraception, however, patient preference is a key consideration. The study population was highly motivated, particularly since women who had difficulty with this means of contraception dropped out after the baseline phase of the trial.

Off-label use. Pharmacokinetic research involving the contraceptive ring has shown that hormone levels required to protect against pregnancy persist for at least 35 days after it is placed in the vagina.⁸ The manufacturer has data only to confirm contraceptive efficacy for up to 28 days and therefore does not recommend use beyond 4 weeks.⁴

This study highlights another off-label issue: Women in Group 2, who were allowed to remove the ring for 4 day-intervals to decrease breakthrough bleeding, were instructed to reinsert the same ring after 4 days and keep it in place until the next scheduled replacement date. But the manufacturer does not recommend reinsertion of a ring that has been out of the body for more than 3 hours. In my practice (KR), women are generally unwilling to store and replace a ring, preferring to place a new one after removal for more than a few hours.

Should she try continuous use?

Changing the ring on the same date each month may boost adherence for some women. Funding. The research was funded by an unrestricted educational grant from Organon, Inc, the manufacturer of NuvaRing, which included salary support for 5 of the 6 authors. The published study gives no additional information about the involvement of the pharmaceutical company.

Contraindications, drug interactions. As with other combined hormonal contraceptives, women who have a history of venous thromboembolism, headaches with focal neurological symptoms, severe hypertension, breast or endometrial cancer, or liver disease, and smokers older than 35 years should not use the contraceptive ring.⁴ In addition, women need to be aware that a number of medications—griseofulvin, rifampin, phenytoin, carbamazepine, and herbal products containing St. John’s Wort, among others—may reduce the effectiveness of the contraceptive ring.⁴

CHALLENGES TO IMPLEMENTATION: Going off-label isn’t for everyone

When it comes to choosing a contraceptive method, patient preference is paramount. Some women may not be comfortable inserting or removing the ring and should be counseled on other forms of contraception. Women who prefer to bleed every month should not use extended cycling. Similarly, some physicians may not be comfortable recommending an off-label use of the ring.

Those who are comfortable making the recommendation should be prepared to educate patients about this method of contraception and to discuss the benefits of extended or continuous use of the ring. For some women, the memory-triggering mechanism of changing the ring on the same date each month may boost adherence. For others, replacing the ring every 28 days may be acceptable—again, depending on patient preference.

Acknowledgements

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

PURLs methodology
This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURLs) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

You’ve known Jane since infancy. Now she’s 15 and in your office for her yearly checkup. As she comes into the exam room, you notice she’s gained a lot of weight since you saw her a year ago. She’s also missing the energy and sparkle that have always been such an engaging part of her personality. When you trot out your usual questions for teens—How’s school? Keeping up your grades? Going out for a team?—her answers are disquieting. School’s dull, her grades have gone downhill, and she’s dropped out of gymnastics. Her mother says Jane is irritable and sleeping a lot, and that worries her.

Could Jane be going through a bout of clinical depression?

Teen depression: Common, and commonly untreated

In North America, about 9% of all teenagers meet the criteria for depression at any given time, and prevalence rates in primary care are very likely higher.¹ One study in the 1990s found approximately 28% of teens presenting to a primary care office met criteria for depression.²

Although adolescents with depression frequently seek care in the primary care setting, most are not identified or treated because of any number of barriers.^3,4 First, mental illness continues to be highly stigmatized. As a result, many troubled teens (and parents of these teens) do not seek help.⁴ Second, mental health professionals trained to treat adolescents are in short supply, and most family physicians and other primary care clinicians feel inadequately trained, supported, or reimbursed for the management of this disorder.⁵ Third, the controversy over the safety and efficacy of antidepressants in the pediatric population has created an additional barrier to care.

In addition, while clinical guidelines for diagnosing and treating adolescent depression have been developed for specialty care settings,⁶ they are not easily transferred to primary care because of the significant differences between the primary and specialty care settings. Recognizing this gap in clinical guidance, a group of researchers and clinicians (including the authors of this report) from the United States and Canada established a collaborative to formulate primary care guidelines for adolescent depression (GuideLines for Adolescent Depression in Primary Care, or GLAD-PC). Details about the collaborative’s methods and recommendations were published in Pediatrics in 2007.^7,8 The accompanying clinician toolkit is available at www.gladpc.org.

This review summarizes the collaborative’s key findings and recommendations and includes evidence from additional research published since the completion of GLAD-PC in 2007. For simplicity’s sake, we use the term “depression” to refer to what is more formally known as major depressive disorder (MDD).

Red flags that you are well positioned to spot

As a family physician, you have the advantage of knowing the families in your practice well and over a long time span. Drawing on that knowledge, you are well placed to spot the red flags that may signal depression in an adolescent patient.

Risk factors for the disorder are well known: a previous episode of depression, a family history of depression, the presence of other psychiatric disorders such as anxiety or attention deficit hyperactivity disorder (ADHD), substance abuse, or life stressors such as bereavement, abuse, or divorce. Teens with depression may complain of emotional problems, or turn up with repeated somatic complaints—headaches, stomach aches, fatigue—that have no apparent physiologic explanation. Their responses to general questions, such as “How is your mood?” or “Have you been sad?” may be worrisome. Or they may screen positive on self-report checklists such as the Beck Depression Inventory (BDI) or the Kutcher Adolescent Depression Scale (KADS), available for download at www.cprf.ca/education/Openmind2006/KADS11.pdf and free for use with permission.^9,10

Routine screening of all adolescents for depression may be feasible, but the US Preventive Services Task Force concluded in 2002 that the evidence was insufficient to recommend for or against the practice.^7,11,12 Expert opinion suggests that among adolescents at elevated risk for depression, depression checklists are useful during well-child and urgent care visits. However, families will likely find general questions more acceptable during acute care visits.¹⁰

“SIGECAPS” mnemonic can help as you evaluate the patient

When you suspect depression, take a detailed history. The diagnostic criteria for depression given in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) are shown in TABLE 1 .^7,10,13 Bear in mind, however, that adolescents who do not meet the full criteria may still be quite impaired and in need of help. The SIGECAPS mnemonic (sleep, interest, guilt, energy, concentration, appetite changes, psychomotor agitation or retardation, suicidality) can help you recall the neurovegetative symptoms in the depression criteria.

Ask about bereavement, manic symptoms (eg, feeling irritable/giddy/silly, hyperactive, racing thoughts), substance use, and life stressors. Ask, too, whether the teen has been treated for mental health problems in the past, and if there is any history of physical or sexual abuse or a family history of mental illness. Because depression is often comorbid with other conditions, you should also inquire about other psychiatric disorders, such as ADHD and anxiety disorders.

The next step. When risk factors or checklists alert you to the possibility of depression, the next step is a more formal evaluation. Because teens and parents often feel uncomfortable disclosing information in the presence of the other, separate interviews are a good idea. Information crucial to the diagnosis may be available only from the adolescent or only from the parent or caregiver, and then only if they are interviewed separately.⁷

Parents may—or may not—pick up on their child’s depression. On the one hand, parents will often have important clues to their child’s diagnosis, such as recent withdrawal from social or extracurricular activities. On the other hand, they may attribute their teen’s behavior to normal adolescent moodiness. Or they might not recognize their teenager’s depression because teens don’t need to be “sad” to be depressed. Sometimes irritability is the major symptom in a depressed teen. (See “How teenage depression is different from that of adults” on page 188.)

Further compounding matters: Since depression is an internalizing disorder, teens may not share their innermost thoughts and emotions with their parents.

TABLE 1
Diagnostic criteria for major depressive episode (DSM-IV-TR)

Is it MDD, or something else?

Although most of the literature on depression is focused on MDD, you should be aware that there are many subtypes of depression, including dysthymia (in which patients have longstanding depressive symptoms but with less functional impairment than major depression) and adjustment disorder (in which patients develop depressive symptoms in response to an acute stressor). As mentioned above, physicians should also assess for psychiatric disorders that are commonly comorbid with depression, because their presence can affect management. These include anxiety disorders, ADHD, eating disorders, and substance abuse.

Ruling out alternative diagnoses. In assessing potentially depressed teenagers like Jane, ruling out conditions with similar symptoms is essential. Medical conditions to be considered in the differential diagnosis are anemia, malignancies, hypothyroidism, and mononucleosis—as well as other viral conditions. There is, however, no evidence to support routine lab testing (including for hypothyroidism) of adolescent patients. Laboratory and other diagnostic evaluation should, instead, be guided by history and targeted physical exam. TABLE 2 presents common medical causes of symptoms of depression that must be considered in the differential diagnosis.

Consider bipolar disorder. Depressive symptoms may also be part of a cycling mood disorder, such as bipolar disorder. In fact, most teens with bipolar disorder will first present with depressive symptoms. Adolescents with depression as part of a bipolar disorder are more likely to have adverse effects with antidepressants than are teens with depression alone. In order to adequately rule out bipolar depression, ask about:

• rapid onset of depressive symptoms: “She just woke up one day and couldn’t stop crying,” for instance
• psychotic symptoms
• family history of bipolar disorder, especially in first-degree relatives
• previous symptoms of mania while on antidepressant treatment (eg, hyperactive, rapid speech, decreased need for sleep).

If a patient has these symptoms or a history of bipolar disorder, refer her or him for a mental health consultation before starting antidepressant treatment.

TABLE 2
Is a medical cause to blame for those symptoms of depression?

Help in classifying the severity of depression

The severity of depression can vary considerably from one patient to another, and distinguishing mild, moderate, and severe depression has significant implications for treatment. Guidelines for grading depression severity are given in TABLE 3 . A common way to classify the severity of a depressive episode is to count the number of symptoms the teenager is displaying.⁷ If all 9 symptoms in the DSM-IV-TR criteria are present, the depression would be classified as severe. But even with fewer symptoms, depression should be considered severe if the teenager is suicidal (has a specific suicide plan, a clear intent, or has made a recent attempt); has psychotic symptoms; or functioning is severely impaired (eg, patient is unable to go to school). The Diagnostic and Statistical Manual of Mental Disorders: Primary Care Version (DSM-PC) is also a useful resource for distinguishing between transient depressive responses and depressive disorders.

TABLE 3
Grading the severity of depressive episodes

Ask yourself: Is this teenager impaired?

Symptoms, in themselves, are not enough to clinch the diagnosis. The fundamental question is whether the symptoms prevent your patient from normal functioning. To judge the extent of a patient’s impairment, you need to assess overall functioning and ask about school, home, friends, and leisure activities. Impairment can be determined by asking the patient and parents the simple questions that every family physician is familiar with:

• How is Jane doing in school? Have her grades slipped lately?
• How is life at home? Does Jane’s mood affect family relationships?
• Does Jane have good friends she can talk to?
• Has her mood affected her ability to maintain friendships?
• What does Jane do for fun? Has she been doing those things lately?

First and foremost, keep your patient safe. Even if you can’t do a complete assessment, your evaluation must at least include the determination of acute risk of harm, either from self-inflicted injury or from impaired judgment. At minimum, assess for suicidality, self-injurious behavior, altered sensorium, substance use, and access to firearms.⁷ Again, this can be aided by the teen’s answers to symptom checklists.

CORRESPONDENCE
Amy Cheung, MD, 33 Russell Street, 3rd Floor Tower, Toronto, Ontario, Canada MSS 2S1; dramy.cheung@gmail.com

You’ve known Jane since infancy. Now she’s 15 and in your office for her yearly checkup. As she comes into the exam room, you notice she’s gained a lot of weight since you saw her a year ago. She’s also missing the energy and sparkle that have always been such an engaging part of her personality. When you trot out your usual questions for teens—How’s school? Keeping up your grades? Going out for a team?—her answers are disquieting. School’s dull, her grades have gone downhill, and she’s dropped out of gymnastics. Her mother says Jane is irritable and sleeping a lot, and that worries her.

Could Jane be going through a bout of clinical depression?

Teen depression: Common, and commonly untreated

In North America, about 9% of all teenagers meet the criteria for depression at any given time, and prevalence rates in primary care are very likely higher.¹ One study in the 1990s found approximately 28% of teens presenting to a primary care office met criteria for depression.²

Although adolescents with depression frequently seek care in the primary care setting, most are not identified or treated because of any number of barriers.^3,4 First, mental illness continues to be highly stigmatized. As a result, many troubled teens (and parents of these teens) do not seek help.⁴ Second, mental health professionals trained to treat adolescents are in short supply, and most family physicians and other primary care clinicians feel inadequately trained, supported, or reimbursed for the management of this disorder.⁵ Third, the controversy over the safety and efficacy of antidepressants in the pediatric population has created an additional barrier to care.

In addition, while clinical guidelines for diagnosing and treating adolescent depression have been developed for specialty care settings,⁶ they are not easily transferred to primary care because of the significant differences between the primary and specialty care settings. Recognizing this gap in clinical guidance, a group of researchers and clinicians (including the authors of this report) from the United States and Canada established a collaborative to formulate primary care guidelines for adolescent depression (GuideLines for Adolescent Depression in Primary Care, or GLAD-PC). Details about the collaborative’s methods and recommendations were published in Pediatrics in 2007.^7,8 The accompanying clinician toolkit is available at www.gladpc.org.

This review summarizes the collaborative’s key findings and recommendations and includes evidence from additional research published since the completion of GLAD-PC in 2007. For simplicity’s sake, we use the term “depression” to refer to what is more formally known as major depressive disorder (MDD).

Red flags that you are well positioned to spot

As a family physician, you have the advantage of knowing the families in your practice well and over a long time span. Drawing on that knowledge, you are well placed to spot the red flags that may signal depression in an adolescent patient.

Risk factors for the disorder are well known: a previous episode of depression, a family history of depression, the presence of other psychiatric disorders such as anxiety or attention deficit hyperactivity disorder (ADHD), substance abuse, or life stressors such as bereavement, abuse, or divorce. Teens with depression may complain of emotional problems, or turn up with repeated somatic complaints—headaches, stomach aches, fatigue—that have no apparent physiologic explanation. Their responses to general questions, such as “How is your mood?” or “Have you been sad?” may be worrisome. Or they may screen positive on self-report checklists such as the Beck Depression Inventory (BDI) or the Kutcher Adolescent Depression Scale (KADS), available for download at www.cprf.ca/education/Openmind2006/KADS11.pdf and free for use with permission.^9,10

Routine screening of all adolescents for depression may be feasible, but the US Preventive Services Task Force concluded in 2002 that the evidence was insufficient to recommend for or against the practice.^7,11,12 Expert opinion suggests that among adolescents at elevated risk for depression, depression checklists are useful during well-child and urgent care visits. However, families will likely find general questions more acceptable during acute care visits.¹⁰

“SIGECAPS” mnemonic can help as you evaluate the patient

When you suspect depression, take a detailed history. The diagnostic criteria for depression given in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) are shown in TABLE 1 .^7,10,13 Bear in mind, however, that adolescents who do not meet the full criteria may still be quite impaired and in need of help. The SIGECAPS mnemonic (sleep, interest, guilt, energy, concentration, appetite changes, psychomotor agitation or retardation, suicidality) can help you recall the neurovegetative symptoms in the depression criteria.

Ask about bereavement, manic symptoms (eg, feeling irritable/giddy/silly, hyperactive, racing thoughts), substance use, and life stressors. Ask, too, whether the teen has been treated for mental health problems in the past, and if there is any history of physical or sexual abuse or a family history of mental illness. Because depression is often comorbid with other conditions, you should also inquire about other psychiatric disorders, such as ADHD and anxiety disorders.

The next step. When risk factors or checklists alert you to the possibility of depression, the next step is a more formal evaluation. Because teens and parents often feel uncomfortable disclosing information in the presence of the other, separate interviews are a good idea. Information crucial to the diagnosis may be available only from the adolescent or only from the parent or caregiver, and then only if they are interviewed separately.⁷

Parents may—or may not—pick up on their child’s depression. On the one hand, parents will often have important clues to their child’s diagnosis, such as recent withdrawal from social or extracurricular activities. On the other hand, they may attribute their teen’s behavior to normal adolescent moodiness. Or they might not recognize their teenager’s depression because teens don’t need to be “sad” to be depressed. Sometimes irritability is the major symptom in a depressed teen. (See “How teenage depression is different from that of adults” on page 188.)

Further compounding matters: Since depression is an internalizing disorder, teens may not share their innermost thoughts and emotions with their parents.

TABLE 1
Diagnostic criteria for major depressive episode (DSM-IV-TR)

Is it MDD, or something else?

Although most of the literature on depression is focused on MDD, you should be aware that there are many subtypes of depression, including dysthymia (in which patients have longstanding depressive symptoms but with less functional impairment than major depression) and adjustment disorder (in which patients develop depressive symptoms in response to an acute stressor). As mentioned above, physicians should also assess for psychiatric disorders that are commonly comorbid with depression, because their presence can affect management. These include anxiety disorders, ADHD, eating disorders, and substance abuse.

Ruling out alternative diagnoses. In assessing potentially depressed teenagers like Jane, ruling out conditions with similar symptoms is essential. Medical conditions to be considered in the differential diagnosis are anemia, malignancies, hypothyroidism, and mononucleosis—as well as other viral conditions. There is, however, no evidence to support routine lab testing (including for hypothyroidism) of adolescent patients. Laboratory and other diagnostic evaluation should, instead, be guided by history and targeted physical exam. TABLE 2 presents common medical causes of symptoms of depression that must be considered in the differential diagnosis.

Consider bipolar disorder. Depressive symptoms may also be part of a cycling mood disorder, such as bipolar disorder. In fact, most teens with bipolar disorder will first present with depressive symptoms. Adolescents with depression as part of a bipolar disorder are more likely to have adverse effects with antidepressants than are teens with depression alone. In order to adequately rule out bipolar depression, ask about:

• rapid onset of depressive symptoms: “She just woke up one day and couldn’t stop crying,” for instance
• psychotic symptoms
• family history of bipolar disorder, especially in first-degree relatives
• previous symptoms of mania while on antidepressant treatment (eg, hyperactive, rapid speech, decreased need for sleep).

If a patient has these symptoms or a history of bipolar disorder, refer her or him for a mental health consultation before starting antidepressant treatment.

TABLE 2
Is a medical cause to blame for those symptoms of depression?

Help in classifying the severity of depression

The severity of depression can vary considerably from one patient to another, and distinguishing mild, moderate, and severe depression has significant implications for treatment. Guidelines for grading depression severity are given in TABLE 3 . A common way to classify the severity of a depressive episode is to count the number of symptoms the teenager is displaying.⁷ If all 9 symptoms in the DSM-IV-TR criteria are present, the depression would be classified as severe. But even with fewer symptoms, depression should be considered severe if the teenager is suicidal (has a specific suicide plan, a clear intent, or has made a recent attempt); has psychotic symptoms; or functioning is severely impaired (eg, patient is unable to go to school). The Diagnostic and Statistical Manual of Mental Disorders: Primary Care Version (DSM-PC) is also a useful resource for distinguishing between transient depressive responses and depressive disorders.

TABLE 3
Grading the severity of depressive episodes

Ask yourself: Is this teenager impaired?

Symptoms, in themselves, are not enough to clinch the diagnosis. The fundamental question is whether the symptoms prevent your patient from normal functioning. To judge the extent of a patient’s impairment, you need to assess overall functioning and ask about school, home, friends, and leisure activities. Impairment can be determined by asking the patient and parents the simple questions that every family physician is familiar with:

• How is Jane doing in school? Have her grades slipped lately?
• How is life at home? Does Jane’s mood affect family relationships?
• Does Jane have good friends she can talk to?
• Has her mood affected her ability to maintain friendships?
• What does Jane do for fun? Has she been doing those things lately?

First and foremost, keep your patient safe. Even if you can’t do a complete assessment, your evaluation must at least include the determination of acute risk of harm, either from self-inflicted injury or from impaired judgment. At minimum, assess for suicidality, self-injurious behavior, altered sensorium, substance use, and access to firearms.⁷ Again, this can be aided by the teen’s answers to symptom checklists.

CORRESPONDENCE
Amy Cheung, MD, 33 Russell Street, 3rd Floor Tower, Toronto, Ontario, Canada MSS 2S1; dramy.cheung@gmail.com

You’ve known Jane since infancy. Now she’s 15 and in your office for her yearly checkup. As she comes into the exam room, you notice she’s gained a lot of weight since you saw her a year ago. She’s also missing the energy and sparkle that have always been such an engaging part of her personality. When you trot out your usual questions for teens—How’s school? Keeping up your grades? Going out for a team?—her answers are disquieting. School’s dull, her grades have gone downhill, and she’s dropped out of gymnastics. Her mother says Jane is irritable and sleeping a lot, and that worries her.

Could Jane be going through a bout of clinical depression?

Teen depression: Common, and commonly untreated

In North America, about 9% of all teenagers meet the criteria for depression at any given time, and prevalence rates in primary care are very likely higher.¹ One study in the 1990s found approximately 28% of teens presenting to a primary care office met criteria for depression.²

Although adolescents with depression frequently seek care in the primary care setting, most are not identified or treated because of any number of barriers.^3,4 First, mental illness continues to be highly stigmatized. As a result, many troubled teens (and parents of these teens) do not seek help.⁴ Second, mental health professionals trained to treat adolescents are in short supply, and most family physicians and other primary care clinicians feel inadequately trained, supported, or reimbursed for the management of this disorder.⁵ Third, the controversy over the safety and efficacy of antidepressants in the pediatric population has created an additional barrier to care.

In addition, while clinical guidelines for diagnosing and treating adolescent depression have been developed for specialty care settings,⁶ they are not easily transferred to primary care because of the significant differences between the primary and specialty care settings. Recognizing this gap in clinical guidance, a group of researchers and clinicians (including the authors of this report) from the United States and Canada established a collaborative to formulate primary care guidelines for adolescent depression (GuideLines for Adolescent Depression in Primary Care, or GLAD-PC). Details about the collaborative’s methods and recommendations were published in Pediatrics in 2007.^7,8 The accompanying clinician toolkit is available at www.gladpc.org.

This review summarizes the collaborative’s key findings and recommendations and includes evidence from additional research published since the completion of GLAD-PC in 2007. For simplicity’s sake, we use the term “depression” to refer to what is more formally known as major depressive disorder (MDD).

Red flags that you are well positioned to spot

As a family physician, you have the advantage of knowing the families in your practice well and over a long time span. Drawing on that knowledge, you are well placed to spot the red flags that may signal depression in an adolescent patient.

Risk factors for the disorder are well known: a previous episode of depression, a family history of depression, the presence of other psychiatric disorders such as anxiety or attention deficit hyperactivity disorder (ADHD), substance abuse, or life stressors such as bereavement, abuse, or divorce. Teens with depression may complain of emotional problems, or turn up with repeated somatic complaints—headaches, stomach aches, fatigue—that have no apparent physiologic explanation. Their responses to general questions, such as “How is your mood?” or “Have you been sad?” may be worrisome. Or they may screen positive on self-report checklists such as the Beck Depression Inventory (BDI) or the Kutcher Adolescent Depression Scale (KADS), available for download at www.cprf.ca/education/Openmind2006/KADS11.pdf and free for use with permission.^9,10

Routine screening of all adolescents for depression may be feasible, but the US Preventive Services Task Force concluded in 2002 that the evidence was insufficient to recommend for or against the practice.^7,11,12 Expert opinion suggests that among adolescents at elevated risk for depression, depression checklists are useful during well-child and urgent care visits. However, families will likely find general questions more acceptable during acute care visits.¹⁰

“SIGECAPS” mnemonic can help as you evaluate the patient

When you suspect depression, take a detailed history. The diagnostic criteria for depression given in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) are shown in TABLE 1 .^7,10,13 Bear in mind, however, that adolescents who do not meet the full criteria may still be quite impaired and in need of help. The SIGECAPS mnemonic (sleep, interest, guilt, energy, concentration, appetite changes, psychomotor agitation or retardation, suicidality) can help you recall the neurovegetative symptoms in the depression criteria.

Ask about bereavement, manic symptoms (eg, feeling irritable/giddy/silly, hyperactive, racing thoughts), substance use, and life stressors. Ask, too, whether the teen has been treated for mental health problems in the past, and if there is any history of physical or sexual abuse or a family history of mental illness. Because depression is often comorbid with other conditions, you should also inquire about other psychiatric disorders, such as ADHD and anxiety disorders.

The next step. When risk factors or checklists alert you to the possibility of depression, the next step is a more formal evaluation. Because teens and parents often feel uncomfortable disclosing information in the presence of the other, separate interviews are a good idea. Information crucial to the diagnosis may be available only from the adolescent or only from the parent or caregiver, and then only if they are interviewed separately.⁷

Parents may—or may not—pick up on their child’s depression. On the one hand, parents will often have important clues to their child’s diagnosis, such as recent withdrawal from social or extracurricular activities. On the other hand, they may attribute their teen’s behavior to normal adolescent moodiness. Or they might not recognize their teenager’s depression because teens don’t need to be “sad” to be depressed. Sometimes irritability is the major symptom in a depressed teen. (See “How teenage depression is different from that of adults” on page 188.)

Further compounding matters: Since depression is an internalizing disorder, teens may not share their innermost thoughts and emotions with their parents.

TABLE 1
Diagnostic criteria for major depressive episode (DSM-IV-TR)

Is it MDD, or something else?

Although most of the literature on depression is focused on MDD, you should be aware that there are many subtypes of depression, including dysthymia (in which patients have longstanding depressive symptoms but with less functional impairment than major depression) and adjustment disorder (in which patients develop depressive symptoms in response to an acute stressor). As mentioned above, physicians should also assess for psychiatric disorders that are commonly comorbid with depression, because their presence can affect management. These include anxiety disorders, ADHD, eating disorders, and substance abuse.

Ruling out alternative diagnoses. In assessing potentially depressed teenagers like Jane, ruling out conditions with similar symptoms is essential. Medical conditions to be considered in the differential diagnosis are anemia, malignancies, hypothyroidism, and mononucleosis—as well as other viral conditions. There is, however, no evidence to support routine lab testing (including for hypothyroidism) of adolescent patients. Laboratory and other diagnostic evaluation should, instead, be guided by history and targeted physical exam. TABLE 2 presents common medical causes of symptoms of depression that must be considered in the differential diagnosis.

Consider bipolar disorder. Depressive symptoms may also be part of a cycling mood disorder, such as bipolar disorder. In fact, most teens with bipolar disorder will first present with depressive symptoms. Adolescents with depression as part of a bipolar disorder are more likely to have adverse effects with antidepressants than are teens with depression alone. In order to adequately rule out bipolar depression, ask about:

• rapid onset of depressive symptoms: “She just woke up one day and couldn’t stop crying,” for instance
• psychotic symptoms
• family history of bipolar disorder, especially in first-degree relatives
• previous symptoms of mania while on antidepressant treatment (eg, hyperactive, rapid speech, decreased need for sleep).

If a patient has these symptoms or a history of bipolar disorder, refer her or him for a mental health consultation before starting antidepressant treatment.

TABLE 2
Is a medical cause to blame for those symptoms of depression?

Help in classifying the severity of depression

The severity of depression can vary considerably from one patient to another, and distinguishing mild, moderate, and severe depression has significant implications for treatment. Guidelines for grading depression severity are given in TABLE 3 . A common way to classify the severity of a depressive episode is to count the number of symptoms the teenager is displaying.⁷ If all 9 symptoms in the DSM-IV-TR criteria are present, the depression would be classified as severe. But even with fewer symptoms, depression should be considered severe if the teenager is suicidal (has a specific suicide plan, a clear intent, or has made a recent attempt); has psychotic symptoms; or functioning is severely impaired (eg, patient is unable to go to school). The Diagnostic and Statistical Manual of Mental Disorders: Primary Care Version (DSM-PC) is also a useful resource for distinguishing between transient depressive responses and depressive disorders.

TABLE 3
Grading the severity of depressive episodes

Ask yourself: Is this teenager impaired?

Symptoms, in themselves, are not enough to clinch the diagnosis. The fundamental question is whether the symptoms prevent your patient from normal functioning. To judge the extent of a patient’s impairment, you need to assess overall functioning and ask about school, home, friends, and leisure activities. Impairment can be determined by asking the patient and parents the simple questions that every family physician is familiar with:

• How is Jane doing in school? Have her grades slipped lately?
• How is life at home? Does Jane’s mood affect family relationships?
• Does Jane have good friends she can talk to?
• Has her mood affected her ability to maintain friendships?
• What does Jane do for fun? Has she been doing those things lately?

First and foremost, keep your patient safe. Even if you can’t do a complete assessment, your evaluation must at least include the determination of acute risk of harm, either from self-inflicted injury or from impaired judgment. At minimum, assess for suicidality, self-injurious behavior, altered sensorium, substance use, and access to firearms.⁷ Again, this can be aided by the teen’s answers to symptom checklists.

CORRESPONDENCE
Amy Cheung, MD, 33 Russell Street, 3rd Floor Tower, Toronto, Ontario, Canada MSS 2S1; dramy.cheung@gmail.com

ILLUSTRATIVE CASE

A 52-year-old man comes to your office complaining of ongoing knee pain—pain that he knows is related to his osteoarthritis (OA). The patient does not want a total knee replacement, and it’s unlikely that his arthritis is extensive enough to warrant it. You wonder whether he’s a potential candidate for arthroscopic knee surgery and if the lavage and articular cartilage debridement the procedure entails would alleviate his symptoms.

Knee pain related to OA is a common complaint in the office setting, and primary care physicians use many medical and physical interventions to manage the symptoms. If these fall short in patients with more advanced disease, however, physicians often recommend an orthopedic surgery consult to consider surgical management.

Lavage and debridement: The (questionable) effects

Arthroscopic knee surgery involves lavage (to remove particulate material, such as cartilage fragments) and debridement (to smooth the articular surfaces). Theoretically, this widely used surgery reduces synovitis and improves joint motion, resulting in a decrease in pain and an improvement in function. But what does the latest research tell us?

A randomized controlled trial (RCT) by Moseley et al in 2002 found arthroscopic knee surgery to be of no benefit for moderate to severe OA.² Because this finding was so contrary to current practice, the authors’ conclusion was not widely accepted. Arthroscopic surgery continued to be used for moderately severe knee arthritis.³ Indeed, the 2008 guidelines from the American Academy of Orthopaedic Surgeons (AAOS) state that “arthroscopic partial meniscectomy or loose body removal is an option in patients with symptomatic OA of the knee who also have primary signs and symptoms of a torn meniscus and/or a loose body.”⁴

However, these guidelines do not include the evidence from the study by Kirkley et al¹ detailed below.

STUDY SUMMARY: New RCT echoes earlier conclusion

Kirkley et al conducted a nonblinded RCT of 188 patients with moderate to severe OA of the knee; those with large meniscal tears, malalignment, previous arthroscopic surgery, or severe bicompartmental arthritis were excluded.

The control group received optimal medical and physical therapy, consisting of 1 hour of physical therapy a week, twice-daily exercises, and stepwise use of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and intraarticular hyaluronic acid injections. The intervention group had arthroscopic surgery (debridement of articular cartilage and menisci, excision of osteophytes, and removal of loose bodies), and received medical and physical therapy.

The primary outcome measure was the validated Western Ontario and McMaster Universities Arthritis Index (WOMAC) score. (The range is 0 to 2400, with higher scores indicating more severe symptoms.)

After 2 years, the researchers found minimal difference in the WOMAC scores of the control group (897±583) and the surgery group (874±624); the absolute difference was –23±605 (95% confidence interval, –208 to 161; P=.22). There was no difference in the secondary outcomes of quality of life, pain, and function. Nor did surgery provide any benefit to the subgroup of patients with mechanical symptoms.¹

These findings echoed those of Moseley et al’s 2002 single-blinded RCT, in which researchers assigned 180 patients to arthroscopic surgery or sham surgery, and found surgery to be of no benefit.² That study was criticized because of its methodology; the researchers used an outcome measure that was not validated and failed to exclude patients with more advanced disease and malalignment, who might be expected to have a poor response to surgery. The 2008 study by Kirkley et al had no such methodological flaws and, in retrospect, it appears that these perceived flaws did not account for the negative findings of the 2002 study.

WHAT’S NEW?: No room for doubt

Evidence from the new RCT confirms the findings of the 2002 trial. It clearly shows that arthroscopic surgery for knee OA is not beneficial, even in patients with mechanical symptoms. Kirkley’s study avoided the criticism of the earlier study by using a validated outcome measure, excluding patients with malalignment, and performing a subgroup analysis of patients with mechanical symptoms. We now have 2 studies that show no benefit from arthroscopic knee surgery in patients with OA, whether or not they have mechanical problems.

So what can you do for patients with moderate to severe knee pain from osteoarthritis? Offer them medical and physical therapy (TABLE) and the assurance that there is nothing to be gained from arthroscopic surgery.

TABLE

How to treat knee OA without surgery

CAVEATS: Large meniscal tears: An exception to the rule

These findings do not necessarily apply to patients with evidence of large meniscal tears. This subset of knee OA patients may benefit from surgical management.

CHALLENGES TO IMPLEMENTATION: What to say to patients seeking a referral

Patients may have read about arthroscopic knee surgery or know someone who underwent the procedure and come to you asking for a referral to an orthopedic surgeon. In such a case, we suggest a straightforward approach.

Discuss arthroscopic surgery’s proven lack of benefit and offer equally effective conservative therapies. For patients who may be eligible for a total knee replacement, a referral to an orthopedic surgeon for evaluation is appropriate.

Acknowledgements

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

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 52-year-old man comes to your office complaining of ongoing knee pain—pain that he knows is related to his osteoarthritis (OA). The patient does not want a total knee replacement, and it’s unlikely that his arthritis is extensive enough to warrant it. You wonder whether he’s a potential candidate for arthroscopic knee surgery and if the lavage and articular cartilage debridement the procedure entails would alleviate his symptoms.

Knee pain related to OA is a common complaint in the office setting, and primary care physicians use many medical and physical interventions to manage the symptoms. If these fall short in patients with more advanced disease, however, physicians often recommend an orthopedic surgery consult to consider surgical management.

Lavage and debridement: The (questionable) effects

Arthroscopic knee surgery involves lavage (to remove particulate material, such as cartilage fragments) and debridement (to smooth the articular surfaces). Theoretically, this widely used surgery reduces synovitis and improves joint motion, resulting in a decrease in pain and an improvement in function. But what does the latest research tell us?

A randomized controlled trial (RCT) by Moseley et al in 2002 found arthroscopic knee surgery to be of no benefit for moderate to severe OA.² Because this finding was so contrary to current practice, the authors’ conclusion was not widely accepted. Arthroscopic surgery continued to be used for moderately severe knee arthritis.³ Indeed, the 2008 guidelines from the American Academy of Orthopaedic Surgeons (AAOS) state that “arthroscopic partial meniscectomy or loose body removal is an option in patients with symptomatic OA of the knee who also have primary signs and symptoms of a torn meniscus and/or a loose body.”⁴

However, these guidelines do not include the evidence from the study by Kirkley et al¹ detailed below.

STUDY SUMMARY: New RCT echoes earlier conclusion

Kirkley et al conducted a nonblinded RCT of 188 patients with moderate to severe OA of the knee; those with large meniscal tears, malalignment, previous arthroscopic surgery, or severe bicompartmental arthritis were excluded.

The control group received optimal medical and physical therapy, consisting of 1 hour of physical therapy a week, twice-daily exercises, and stepwise use of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and intraarticular hyaluronic acid injections. The intervention group had arthroscopic surgery (debridement of articular cartilage and menisci, excision of osteophytes, and removal of loose bodies), and received medical and physical therapy.

The primary outcome measure was the validated Western Ontario and McMaster Universities Arthritis Index (WOMAC) score. (The range is 0 to 2400, with higher scores indicating more severe symptoms.)

After 2 years, the researchers found minimal difference in the WOMAC scores of the control group (897±583) and the surgery group (874±624); the absolute difference was –23±605 (95% confidence interval, –208 to 161; P=.22). There was no difference in the secondary outcomes of quality of life, pain, and function. Nor did surgery provide any benefit to the subgroup of patients with mechanical symptoms.¹

These findings echoed those of Moseley et al’s 2002 single-blinded RCT, in which researchers assigned 180 patients to arthroscopic surgery or sham surgery, and found surgery to be of no benefit.² That study was criticized because of its methodology; the researchers used an outcome measure that was not validated and failed to exclude patients with more advanced disease and malalignment, who might be expected to have a poor response to surgery. The 2008 study by Kirkley et al had no such methodological flaws and, in retrospect, it appears that these perceived flaws did not account for the negative findings of the 2002 study.

WHAT’S NEW?: No room for doubt

Evidence from the new RCT confirms the findings of the 2002 trial. It clearly shows that arthroscopic surgery for knee OA is not beneficial, even in patients with mechanical symptoms. Kirkley’s study avoided the criticism of the earlier study by using a validated outcome measure, excluding patients with malalignment, and performing a subgroup analysis of patients with mechanical symptoms. We now have 2 studies that show no benefit from arthroscopic knee surgery in patients with OA, whether or not they have mechanical problems.

So what can you do for patients with moderate to severe knee pain from osteoarthritis? Offer them medical and physical therapy (TABLE) and the assurance that there is nothing to be gained from arthroscopic surgery.

TABLE

How to treat knee OA without surgery

CAVEATS: Large meniscal tears: An exception to the rule

These findings do not necessarily apply to patients with evidence of large meniscal tears. This subset of knee OA patients may benefit from surgical management.

CHALLENGES TO IMPLEMENTATION: What to say to patients seeking a referral

Patients may have read about arthroscopic knee surgery or know someone who underwent the procedure and come to you asking for a referral to an orthopedic surgeon. In such a case, we suggest a straightforward approach.

Discuss arthroscopic surgery’s proven lack of benefit and offer equally effective conservative therapies. For patients who may be eligible for a total knee replacement, a referral to an orthopedic surgeon for evaluation is appropriate.

Acknowledgements

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

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 52-year-old man comes to your office complaining of ongoing knee pain—pain that he knows is related to his osteoarthritis (OA). The patient does not want a total knee replacement, and it’s unlikely that his arthritis is extensive enough to warrant it. You wonder whether he’s a potential candidate for arthroscopic knee surgery and if the lavage and articular cartilage debridement the procedure entails would alleviate his symptoms.

Knee pain related to OA is a common complaint in the office setting, and primary care physicians use many medical and physical interventions to manage the symptoms. If these fall short in patients with more advanced disease, however, physicians often recommend an orthopedic surgery consult to consider surgical management.

Lavage and debridement: The (questionable) effects

Arthroscopic knee surgery involves lavage (to remove particulate material, such as cartilage fragments) and debridement (to smooth the articular surfaces). Theoretically, this widely used surgery reduces synovitis and improves joint motion, resulting in a decrease in pain and an improvement in function. But what does the latest research tell us?

A randomized controlled trial (RCT) by Moseley et al in 2002 found arthroscopic knee surgery to be of no benefit for moderate to severe OA.² Because this finding was so contrary to current practice, the authors’ conclusion was not widely accepted. Arthroscopic surgery continued to be used for moderately severe knee arthritis.³ Indeed, the 2008 guidelines from the American Academy of Orthopaedic Surgeons (AAOS) state that “arthroscopic partial meniscectomy or loose body removal is an option in patients with symptomatic OA of the knee who also have primary signs and symptoms of a torn meniscus and/or a loose body.”⁴

However, these guidelines do not include the evidence from the study by Kirkley et al¹ detailed below.

STUDY SUMMARY: New RCT echoes earlier conclusion

Kirkley et al conducted a nonblinded RCT of 188 patients with moderate to severe OA of the knee; those with large meniscal tears, malalignment, previous arthroscopic surgery, or severe bicompartmental arthritis were excluded.

The control group received optimal medical and physical therapy, consisting of 1 hour of physical therapy a week, twice-daily exercises, and stepwise use of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and intraarticular hyaluronic acid injections. The intervention group had arthroscopic surgery (debridement of articular cartilage and menisci, excision of osteophytes, and removal of loose bodies), and received medical and physical therapy.

The primary outcome measure was the validated Western Ontario and McMaster Universities Arthritis Index (WOMAC) score. (The range is 0 to 2400, with higher scores indicating more severe symptoms.)

After 2 years, the researchers found minimal difference in the WOMAC scores of the control group (897±583) and the surgery group (874±624); the absolute difference was –23±605 (95% confidence interval, –208 to 161; P=.22). There was no difference in the secondary outcomes of quality of life, pain, and function. Nor did surgery provide any benefit to the subgroup of patients with mechanical symptoms.¹

These findings echoed those of Moseley et al’s 2002 single-blinded RCT, in which researchers assigned 180 patients to arthroscopic surgery or sham surgery, and found surgery to be of no benefit.² That study was criticized because of its methodology; the researchers used an outcome measure that was not validated and failed to exclude patients with more advanced disease and malalignment, who might be expected to have a poor response to surgery. The 2008 study by Kirkley et al had no such methodological flaws and, in retrospect, it appears that these perceived flaws did not account for the negative findings of the 2002 study.

WHAT’S NEW?: No room for doubt

Evidence from the new RCT confirms the findings of the 2002 trial. It clearly shows that arthroscopic surgery for knee OA is not beneficial, even in patients with mechanical symptoms. Kirkley’s study avoided the criticism of the earlier study by using a validated outcome measure, excluding patients with malalignment, and performing a subgroup analysis of patients with mechanical symptoms. We now have 2 studies that show no benefit from arthroscopic knee surgery in patients with OA, whether or not they have mechanical problems.

So what can you do for patients with moderate to severe knee pain from osteoarthritis? Offer them medical and physical therapy (TABLE) and the assurance that there is nothing to be gained from arthroscopic surgery.

TABLE

How to treat knee OA without surgery

CAVEATS: Large meniscal tears: An exception to the rule

These findings do not necessarily apply to patients with evidence of large meniscal tears. This subset of knee OA patients may benefit from surgical management.

CHALLENGES TO IMPLEMENTATION: What to say to patients seeking a referral

Patients may have read about arthroscopic knee surgery or know someone who underwent the procedure and come to you asking for a referral to an orthopedic surgeon. In such a case, we suggest a straightforward approach.

Discuss arthroscopic surgery’s proven lack of benefit and offer equally effective conservative therapies. For patients who may be eligible for a total knee replacement, a referral to an orthopedic surgeon for evaluation is appropriate.

Acknowledgements

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

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

Sarah, a 2-year-old who has been vomiting and had diarrhea for the past 2 days, is brought to your office by her parents. They tell you she’s unable to tolerate oral fluids, and vomited twice after being given small amounts of juice and soup earlier in the day. Sarah has decreased urine output, but she is not febrile and has no blood in her stools. On examination, you find mild tachycardia, dry mucous membranes, delayed capillary refill, and normal mental status.

You try giving Sarah an oral electrolyte solution, but she vomits immediately. Her parents are reluctant to take her to the emergency department for intravenous (IV) hydration, and ask if you can provide a safe and effective alternative.

Each year in the United States, pediatric gastroenteritis and dehydration are responsible for approximately 1.5 million outpatient visits² and 150,000 to 170,000 hospital admissions.³ Oral hydration, recommended by pediatric practice guidelines^2,4 and the World Health Organization,⁵ is safe and generally effective. But, as in Sarah’s case, emesis frequently interferes, leading to hospital admission for IV hydration.

An antiemetic with fewer adverse effects

Older antiemetic medications, such as promethazine, prochlorperazine, and metoclopramide, can cause sedation and extrapyramidal reactions. Ondansetron, a selective 5-hydroxytryptamine (5-HT₃) receptor antagonist that has been used to control postoperative and chemotherapy-associated nausea and vomiting in children and adults, does not cause either problem. In recent studies of ondansetron’s effectiveness in treating children with gastroenteritis, increased diarrhea, lasting up to 48 hours after administration, was the only adverse event.¹

Two earlier systematic reviews—a meta-analysis by Szajewska et al⁶ and a Cochrane review⁷—found clinical benefits of ondansetron for vomiting associated with acute gastroenteritis. But both concluded that the evidence was insufficient to recommend routine use of this drug. The meta-analysis that we review below included additional studies, and the researchers reached a different conclusion.

STUDY SUMMARY: Antiemetic decreases vomiting, hospitalization

DeCamp et al conducted a systematic review and meta-analysis of 11 prospective controlled trials that evaluated antiemetic use in children with vomiting from acute gastroenteritis.¹ Six of the 11 trials focused on ondansetron;^8-13 these 6 were the most recently published and of the highest quality. (The researchers found the remaining 5 trials to be of low methodological quality, with small sample sizes and inconsistent results, and concluded that the antiemetics they assessed should not be used for outpatients with gastroenteritis.) Their meta-analysis of these 6 trials is the focus of this PURL.

The ondansetron studies included a total of 745 children with vomiting and a clinical diagnosis of gastroenteritis. In 5 of the trials, patients received only 1 dose of ondansetron;^8-10,12,13 in the sixth, families received additional doses of ondansetron to use at home.¹¹ In 3 trials, patients were given oral ondansetron—a tablet placed on the tongue that dissolves in minutes. The remaining 3 used an IV formulation.^8,10,13 Five trials were conducted in emergency departments (EDs),^9-13 and 1 in an inpatient setting.⁸

Big reductions. Children who received ondansetron had significantly less vomiting (16.9% vs 37.8%) and IV fluid administration (13.9% vs 33.9%), and fewer hospital admissions (7.5% vs 14.6%) compared with patients who were given a placebo (TABLE). Diarrhea, the only adverse event to be systematically evaluated, was assessed in all but 1 of the trials.^8-12 In 3 of the 5 that reported on this side effect, patients who received ondansetron had an increase in diarrhea for up to 48 hours.^8,11,12

TABLE
Ondansetron reduces vomiting, hospitalization, and IV fluid use

WHAT’S NEW: Support for a strategy increasingly used in EDs

Physicians are just beginning to adopt the use of ondansetron as a strategy for avoiding IV hydration and hospitalization for children with vomiting associated with minor gastrointestinal illness. As an adjunct to our report on this meta-analysis, we analyzed the use of the antiemetic in children between the ages of 1 and 10 years in emergency visits reported to the National Ambulatory Medical Care Survey database from 2002 to 2006. Among an estimate of more than 3 million pediatric visits to EDs for acute gastroenteritis in each of these years, in 2002 only 0.53% were treated with ondansetron. By 2006, that percentage had risen to 6.43%.

A similar analysis of both ED and outpatient visits to academic medical centers and teaching hospitals from 2005 through 2008 (estimated using data through October 2008), derived from the University Health System Consortium Clinical Database, showed a similar trend. In 2005, only 0.5% of children presenting to EDs and 0.5% of those seeking outpatient care for acute gastritis received ondansetron. By 2008, the numbers had grown to an estimated 3.43% and 3.60%, respectively.

Given the positive results of the DeCamp study and the fact that oral ondansetron is now available in a generic formulation, we expect the use of this antiemetic to increase in both outpatient and emergency settings. We think quite a few IV lines and hospitalizations could be avoided with the use of this antiemetic, not to mention the symptomatic relief for children.

CAVEATS: Studies didn’t look at milder cases, primary care

None of the studies of oral ondansetron for acute gastroenteritis involved outpatient settings, and all 6 of the trials featured children who were moderately ill. It has not yet been determined whether the benefits seen in the ED will apply to an ambulatory population in which many potential candidates for ondansetron have milder gastroenteritis. Nor is it clear whether oral ondansetron would complement oral rehydration in primary care practices. More detailed evaluation of the reduction of vomiting at home over the course of the illness would help to answer these questions.

Nonetheless, ondansetron appears to be safe. Increased diarrhea, the only documented side effect, resolved after 48 hours, and did not appear to result in higher health care utilization.

Don’t prescribe over the phone. It is important to note that all the ondansetron trials included an evaluation of each patient to consider other etiologies, such as central nervous system disorders or toxic exposures, prior to treatment. Physicians are cautioned not to prescribe antiemetics over the telephone—or without first ruling out more serious illnesses in which vomiting is part of the presentation.

Studies were funded by pharma. The primary studies of ondansetron were funded by GlaxoSmithKline, the pharmaceutical company that manufactures the drug under the trade name Zofran. The authors of the meta-analysis reviewed the Clinical Trials Registry and the reference lists of the articles and contacted other experts to find any unreported trials, but found no evidence of negative publication bias. Therefore, we have confidence in these findings. Ideally, additional studies will be conducted without drug company support, in an outpatient setting, to clarify the use of ondansetron as an adjunct to oral rehydration.

CHALLENGES TO IMPLEMENTATION: No major barriers

Cost should not be a barrier to the use of oral ondansetron. The generic formulation sells for $10 to $20 per tablet, and is covered by most health insurers. However, treatment of children with acute gastroenteritis and moderate dehydration in the office setting would likely require a period of observation for tolerance of oral rehydration before and after administration of ondansetron. This may be impractical in some busy clinics.

Acknowledgements

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

The authors wish to acknowledge Sofia Medvedev, PhD, of the University HealthSystem Consortium in Oak Brook, Ill, for analysis of the National Ambulatory Medical Care Survey data and the UHC Clinical Database.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

Sarah, a 2-year-old who has been vomiting and had diarrhea for the past 2 days, is brought to your office by her parents. They tell you she’s unable to tolerate oral fluids, and vomited twice after being given small amounts of juice and soup earlier in the day. Sarah has decreased urine output, but she is not febrile and has no blood in her stools. On examination, you find mild tachycardia, dry mucous membranes, delayed capillary refill, and normal mental status.

You try giving Sarah an oral electrolyte solution, but she vomits immediately. Her parents are reluctant to take her to the emergency department for intravenous (IV) hydration, and ask if you can provide a safe and effective alternative.

Each year in the United States, pediatric gastroenteritis and dehydration are responsible for approximately 1.5 million outpatient visits² and 150,000 to 170,000 hospital admissions.³ Oral hydration, recommended by pediatric practice guidelines^2,4 and the World Health Organization,⁵ is safe and generally effective. But, as in Sarah’s case, emesis frequently interferes, leading to hospital admission for IV hydration.

An antiemetic with fewer adverse effects

Older antiemetic medications, such as promethazine, prochlorperazine, and metoclopramide, can cause sedation and extrapyramidal reactions. Ondansetron, a selective 5-hydroxytryptamine (5-HT₃) receptor antagonist that has been used to control postoperative and chemotherapy-associated nausea and vomiting in children and adults, does not cause either problem. In recent studies of ondansetron’s effectiveness in treating children with gastroenteritis, increased diarrhea, lasting up to 48 hours after administration, was the only adverse event.¹

Two earlier systematic reviews—a meta-analysis by Szajewska et al⁶ and a Cochrane review⁷—found clinical benefits of ondansetron for vomiting associated with acute gastroenteritis. But both concluded that the evidence was insufficient to recommend routine use of this drug. The meta-analysis that we review below included additional studies, and the researchers reached a different conclusion.

STUDY SUMMARY: Antiemetic decreases vomiting, hospitalization

DeCamp et al conducted a systematic review and meta-analysis of 11 prospective controlled trials that evaluated antiemetic use in children with vomiting from acute gastroenteritis.¹ Six of the 11 trials focused on ondansetron;^8-13 these 6 were the most recently published and of the highest quality. (The researchers found the remaining 5 trials to be of low methodological quality, with small sample sizes and inconsistent results, and concluded that the antiemetics they assessed should not be used for outpatients with gastroenteritis.) Their meta-analysis of these 6 trials is the focus of this PURL.

The ondansetron studies included a total of 745 children with vomiting and a clinical diagnosis of gastroenteritis. In 5 of the trials, patients received only 1 dose of ondansetron;^8-10,12,13 in the sixth, families received additional doses of ondansetron to use at home.¹¹ In 3 trials, patients were given oral ondansetron—a tablet placed on the tongue that dissolves in minutes. The remaining 3 used an IV formulation.^8,10,13 Five trials were conducted in emergency departments (EDs),^9-13 and 1 in an inpatient setting.⁸

Big reductions. Children who received ondansetron had significantly less vomiting (16.9% vs 37.8%) and IV fluid administration (13.9% vs 33.9%), and fewer hospital admissions (7.5% vs 14.6%) compared with patients who were given a placebo (TABLE). Diarrhea, the only adverse event to be systematically evaluated, was assessed in all but 1 of the trials.^8-12 In 3 of the 5 that reported on this side effect, patients who received ondansetron had an increase in diarrhea for up to 48 hours.^8,11,12

TABLE
Ondansetron reduces vomiting, hospitalization, and IV fluid use

WHAT’S NEW: Support for a strategy increasingly used in EDs

Physicians are just beginning to adopt the use of ondansetron as a strategy for avoiding IV hydration and hospitalization for children with vomiting associated with minor gastrointestinal illness. As an adjunct to our report on this meta-analysis, we analyzed the use of the antiemetic in children between the ages of 1 and 10 years in emergency visits reported to the National Ambulatory Medical Care Survey database from 2002 to 2006. Among an estimate of more than 3 million pediatric visits to EDs for acute gastroenteritis in each of these years, in 2002 only 0.53% were treated with ondansetron. By 2006, that percentage had risen to 6.43%.

A similar analysis of both ED and outpatient visits to academic medical centers and teaching hospitals from 2005 through 2008 (estimated using data through October 2008), derived from the University Health System Consortium Clinical Database, showed a similar trend. In 2005, only 0.5% of children presenting to EDs and 0.5% of those seeking outpatient care for acute gastritis received ondansetron. By 2008, the numbers had grown to an estimated 3.43% and 3.60%, respectively.

Given the positive results of the DeCamp study and the fact that oral ondansetron is now available in a generic formulation, we expect the use of this antiemetic to increase in both outpatient and emergency settings. We think quite a few IV lines and hospitalizations could be avoided with the use of this antiemetic, not to mention the symptomatic relief for children.

CAVEATS: Studies didn’t look at milder cases, primary care

None of the studies of oral ondansetron for acute gastroenteritis involved outpatient settings, and all 6 of the trials featured children who were moderately ill. It has not yet been determined whether the benefits seen in the ED will apply to an ambulatory population in which many potential candidates for ondansetron have milder gastroenteritis. Nor is it clear whether oral ondansetron would complement oral rehydration in primary care practices. More detailed evaluation of the reduction of vomiting at home over the course of the illness would help to answer these questions.

Nonetheless, ondansetron appears to be safe. Increased diarrhea, the only documented side effect, resolved after 48 hours, and did not appear to result in higher health care utilization.

Don’t prescribe over the phone. It is important to note that all the ondansetron trials included an evaluation of each patient to consider other etiologies, such as central nervous system disorders or toxic exposures, prior to treatment. Physicians are cautioned not to prescribe antiemetics over the telephone—or without first ruling out more serious illnesses in which vomiting is part of the presentation.

Studies were funded by pharma. The primary studies of ondansetron were funded by GlaxoSmithKline, the pharmaceutical company that manufactures the drug under the trade name Zofran. The authors of the meta-analysis reviewed the Clinical Trials Registry and the reference lists of the articles and contacted other experts to find any unreported trials, but found no evidence of negative publication bias. Therefore, we have confidence in these findings. Ideally, additional studies will be conducted without drug company support, in an outpatient setting, to clarify the use of ondansetron as an adjunct to oral rehydration.

CHALLENGES TO IMPLEMENTATION: No major barriers

Cost should not be a barrier to the use of oral ondansetron. The generic formulation sells for $10 to $20 per tablet, and is covered by most health insurers. However, treatment of children with acute gastroenteritis and moderate dehydration in the office setting would likely require a period of observation for tolerance of oral rehydration before and after administration of ondansetron. This may be impractical in some busy clinics.

Acknowledgements

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

The authors wish to acknowledge Sofia Medvedev, PhD, of the University HealthSystem Consortium in Oak Brook, Ill, for analysis of the National Ambulatory Medical Care Survey data and the UHC Clinical Database.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

Sarah, a 2-year-old who has been vomiting and had diarrhea for the past 2 days, is brought to your office by her parents. They tell you she’s unable to tolerate oral fluids, and vomited twice after being given small amounts of juice and soup earlier in the day. Sarah has decreased urine output, but she is not febrile and has no blood in her stools. On examination, you find mild tachycardia, dry mucous membranes, delayed capillary refill, and normal mental status.

You try giving Sarah an oral electrolyte solution, but she vomits immediately. Her parents are reluctant to take her to the emergency department for intravenous (IV) hydration, and ask if you can provide a safe and effective alternative.

Each year in the United States, pediatric gastroenteritis and dehydration are responsible for approximately 1.5 million outpatient visits² and 150,000 to 170,000 hospital admissions.³ Oral hydration, recommended by pediatric practice guidelines^2,4 and the World Health Organization,⁵ is safe and generally effective. But, as in Sarah’s case, emesis frequently interferes, leading to hospital admission for IV hydration.

An antiemetic with fewer adverse effects

Older antiemetic medications, such as promethazine, prochlorperazine, and metoclopramide, can cause sedation and extrapyramidal reactions. Ondansetron, a selective 5-hydroxytryptamine (5-HT₃) receptor antagonist that has been used to control postoperative and chemotherapy-associated nausea and vomiting in children and adults, does not cause either problem. In recent studies of ondansetron’s effectiveness in treating children with gastroenteritis, increased diarrhea, lasting up to 48 hours after administration, was the only adverse event.¹

Two earlier systematic reviews—a meta-analysis by Szajewska et al⁶ and a Cochrane review⁷—found clinical benefits of ondansetron for vomiting associated with acute gastroenteritis. But both concluded that the evidence was insufficient to recommend routine use of this drug. The meta-analysis that we review below included additional studies, and the researchers reached a different conclusion.

STUDY SUMMARY: Antiemetic decreases vomiting, hospitalization

DeCamp et al conducted a systematic review and meta-analysis of 11 prospective controlled trials that evaluated antiemetic use in children with vomiting from acute gastroenteritis.¹ Six of the 11 trials focused on ondansetron;^8-13 these 6 were the most recently published and of the highest quality. (The researchers found the remaining 5 trials to be of low methodological quality, with small sample sizes and inconsistent results, and concluded that the antiemetics they assessed should not be used for outpatients with gastroenteritis.) Their meta-analysis of these 6 trials is the focus of this PURL.

The ondansetron studies included a total of 745 children with vomiting and a clinical diagnosis of gastroenteritis. In 5 of the trials, patients received only 1 dose of ondansetron;^8-10,12,13 in the sixth, families received additional doses of ondansetron to use at home.¹¹ In 3 trials, patients were given oral ondansetron—a tablet placed on the tongue that dissolves in minutes. The remaining 3 used an IV formulation.^8,10,13 Five trials were conducted in emergency departments (EDs),^9-13 and 1 in an inpatient setting.⁸

Big reductions. Children who received ondansetron had significantly less vomiting (16.9% vs 37.8%) and IV fluid administration (13.9% vs 33.9%), and fewer hospital admissions (7.5% vs 14.6%) compared with patients who were given a placebo (TABLE). Diarrhea, the only adverse event to be systematically evaluated, was assessed in all but 1 of the trials.^8-12 In 3 of the 5 that reported on this side effect, patients who received ondansetron had an increase in diarrhea for up to 48 hours.^8,11,12

TABLE
Ondansetron reduces vomiting, hospitalization, and IV fluid use

WHAT’S NEW: Support for a strategy increasingly used in EDs

Physicians are just beginning to adopt the use of ondansetron as a strategy for avoiding IV hydration and hospitalization for children with vomiting associated with minor gastrointestinal illness. As an adjunct to our report on this meta-analysis, we analyzed the use of the antiemetic in children between the ages of 1 and 10 years in emergency visits reported to the National Ambulatory Medical Care Survey database from 2002 to 2006. Among an estimate of more than 3 million pediatric visits to EDs for acute gastroenteritis in each of these years, in 2002 only 0.53% were treated with ondansetron. By 2006, that percentage had risen to 6.43%.

A similar analysis of both ED and outpatient visits to academic medical centers and teaching hospitals from 2005 through 2008 (estimated using data through October 2008), derived from the University Health System Consortium Clinical Database, showed a similar trend. In 2005, only 0.5% of children presenting to EDs and 0.5% of those seeking outpatient care for acute gastritis received ondansetron. By 2008, the numbers had grown to an estimated 3.43% and 3.60%, respectively.

Given the positive results of the DeCamp study and the fact that oral ondansetron is now available in a generic formulation, we expect the use of this antiemetic to increase in both outpatient and emergency settings. We think quite a few IV lines and hospitalizations could be avoided with the use of this antiemetic, not to mention the symptomatic relief for children.

CAVEATS: Studies didn’t look at milder cases, primary care

None of the studies of oral ondansetron for acute gastroenteritis involved outpatient settings, and all 6 of the trials featured children who were moderately ill. It has not yet been determined whether the benefits seen in the ED will apply to an ambulatory population in which many potential candidates for ondansetron have milder gastroenteritis. Nor is it clear whether oral ondansetron would complement oral rehydration in primary care practices. More detailed evaluation of the reduction of vomiting at home over the course of the illness would help to answer these questions.

Nonetheless, ondansetron appears to be safe. Increased diarrhea, the only documented side effect, resolved after 48 hours, and did not appear to result in higher health care utilization.

Don’t prescribe over the phone. It is important to note that all the ondansetron trials included an evaluation of each patient to consider other etiologies, such as central nervous system disorders or toxic exposures, prior to treatment. Physicians are cautioned not to prescribe antiemetics over the telephone—or without first ruling out more serious illnesses in which vomiting is part of the presentation.

Studies were funded by pharma. The primary studies of ondansetron were funded by GlaxoSmithKline, the pharmaceutical company that manufactures the drug under the trade name Zofran. The authors of the meta-analysis reviewed the Clinical Trials Registry and the reference lists of the articles and contacted other experts to find any unreported trials, but found no evidence of negative publication bias. Therefore, we have confidence in these findings. Ideally, additional studies will be conducted without drug company support, in an outpatient setting, to clarify the use of ondansetron as an adjunct to oral rehydration.

CHALLENGES TO IMPLEMENTATION: No major barriers

Cost should not be a barrier to the use of oral ondansetron. The generic formulation sells for $10 to $20 per tablet, and is covered by most health insurers. However, treatment of children with acute gastroenteritis and moderate dehydration in the office setting would likely require a period of observation for tolerance of oral rehydration before and after administration of ondansetron. This may be impractical in some busy clinics.

Acknowledgements

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

The authors wish to acknowledge Sofia Medvedev, PhD, of the University HealthSystem Consortium in Oak Brook, Ill, for analysis of the National Ambulatory Medical Care Survey data and the UHC Clinical Database.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 45-year-old woman presents to your office with an 8-month history of nasal congestion and thick nasal discharge. Her symptoms have waxed and waned, the patient reports. She’s tried decongestants, antibiotics, and nasal steroids, with limited success. The patient has not had a recent respiratory infection, has never had sinus surgery, and does not want to be on long-term medication. You wonder if there’s an alternative treatment you can offer.

Rhinosinusitis is one of the most common conditions seen by primary care physicians in the United States, and its incidence and prevalence are increasing.^2,3 While acute rhinosinusitis is usually self-limiting and resolves within a month, some patients develop chronic—and hard to treat—sinonasal symptoms.

No single cause, no definitive treatment

We’ve moved away from the notion that chronic rhinosinusitis is always a manifestation of persistent bacterial infection, and now recognize that there’s an inflammatory, nonbacterial component.⁴ In any given patient, several mechanisms—acting either simultaneously or independently—may contribute to sinonasal symptoms.³

Chronic sinusitis is treated in a variety of ways, including medications, immunotherapy, and surgery. Despite their limited efficacy, antibiotics and nasal steroids have been the mainstays of treatment.⁵ Treating underlying allergies, when they exist, may be helpful. But regardless of which treatment patients receive for chronic rhinosinusitis, many remain symptomatic.⁶

Benefits of saline irrigation extend beyond postop care

Otolaryngologists recommend saline irrigation after sinus surgery to clear secretions, debris, and crusts; reduce the risk of postoperative mucosal adhesions; and expedite mucosal healing.^7,8 Saline irrigation is also gaining popularity as an alternative approach to chronic sinusitis symptom relief, and several randomized controlled trials (RCTs) have demonstrated both objective and subjective efficacy of this treatment for sinonasal disease.^8-11

In 2007, the Cochrane Collaboration reviewed evidence for the effectiveness of nasal saline irrigation for symptoms of chronic rhinosinusitis. The reviewers concluded that it is well tolerated and beneficial, whether used alone or as an adjunctive treatment.¹²

Nasal saline sprays are often recommended because they’re thought to be better tolerated than other delivery modes.¹³ There have, however, been no comparisons of the relative efficacy of different means of saline delivery, until now.

STUDY SUMMARY: Nasal irrigation and spray go head-to-head

This study was a high-quality, prospective RCT comparing nasal spray and nasal irrigation.¹ Subjects were recruited from the general population. To be eligible, participants had to be 18 years of age or older and have reported at least one of the following chronic rhinosinusitis symptoms on 4 or more days each week in the preceding 2 weeks:

• nasal stuffiness
• nasal dryness or crusting
• nasal congestion
• thick or discolored nasal discharge.

In addition, the symptoms must have been present on at least 15 of the preceding 30 days. Exclusion criteria included recent sinus surgery, a respiratory infection within the past 2 weeks, and the use of nasal saline within the past month.

Researchers enrolled 127 patients in the study; 63 were randomized to the nasal spray group and 64 to the large-volume, low-pressure irrigation group. Demographic and baseline characteristics of the groups were similar. The average ages of those in the irrigation and spray groups were 45 and 48 years, respectively. Most patients were nonsmokers and had been symptomatic for 7 to 12 months.

Twice-daily treatment. Researchers asked the patients to perform the assigned treatment twice daily for 8 weeks, but the patients were also permitted to continue using their usual medications. Symptom severity and disease-specific quality of life were assessed with the Sino-Nasal Outcome Test (SNOT-20), a 20-item survey that measures physical problems, emotional consequences, and functional limitations of sinusitis.¹⁴

The SNOT-20 is a validated, self-administered survey that asks patients to score items such as runny nose, postnasal discharge, need to blow the nose, reduced productivity, and embarrassment, on a 0- to 5-point scale (0=never, 5=always). A SNOT-20 score of 100 indicates the worst possible symptoms.

As a measure of chronicity of symptoms, patients were also asked to estimate how many months they’d had these symptoms during the last year. In addition, they were instructed to keep a diary to document treatment compliance and the use of other medications for sinonasal symptoms.

To measure outcomes, the researchers provided patients with mail-in packets so they could send in their completed SNOT-20 questionnaire and the medication diary completed at 2, 4, and 8 weeks after randomization.

Biggest improvements seen in irrigation group

Severity of symptoms. In each outcome measurement period, the saline irrigation group had lower SNOT-20 scores than the nasal spray group. At 2 weeks, the irrigation group scores were 4.4 points lower than the spray group (P=.02); at 4 weeks, the scores were 8.2 points lower (P<.001), and at 8 weeks the scores were 6.4 points lower (P=.002). Those in the irrigation group also had a significantly greater change from baseline than the patients in the spray group at 4 weeks (16.2 vs 7.4, P=.002) and at 8 weeks (15.0 vs 8.5, P=.04). The difference was marginally significant at 2 weeks (12.2 vs 6.7, P=.05).

Frequency of symptoms. At 8 weeks, 40% of the irrigation group and 61% of the nasal spray group reported nasal or sinus symptoms “often or always.” The absolute risk reduction in symptom frequency with saline irrigations, therefore, was 0.21; 95% confidence interval, 0.02-0.38 (P=.01). The odds of frequent nasal symptoms were 50% lower in the irrigation group compared to the spray group.

WHAT’S NEW: One delivery method is better than another

Prior studies had proven the effectiveness of nasal saline for reduction of rhinosinusitis symptoms. This RCT demonstrated that large-volume, low-pressure nasal irrigation brings greater symptom relief than nasal spray.

The researchers found little difference between the 2 groups in the rate of adverse effects, and reported that nasal irrigation appears to be well accepted once patients become accustomed to it. The fact that the participants were recruited from the general population further suggests that the results will be generalizable to primary care patients.

CAVEATS: High dropout rate in irrigation group

The absence of a control group prevents us from knowing the effect of saline nasal spray or irrigation compared with no treatment. In prior studies, however, nasal saline spray was found to be more effective than placebo in reducing rhinosinusitis symptoms.^8,15

It is notable that a significant portion (21%) of the irrigation group abandoned this treatment by 8 weeks; in comparison, just 7% of the nasal spray group discontinued treatment.

This lower rate of adherence makes the beneficial effects of the irrigation group even more impressive. But it also suggests that a significant portion of patients are unlikely to stay with this recommended regimen. For those who try saline irrigation and choose not to continue it or are unwilling even to try it, saline spray is a reasonable alternative.

It should be noted that financial support for this study was provided by NeilMed Pharmaceuticals, a manufacturer of nasal saline solution and irrigation devices. However, the sponsor was not involved in the design or conduct of the study, in data collection or analysis, or in the preparation of the manuscript.

CHALLENGES TO IMPLEMENTATION: Tx may “scare away” some patients

Despite its effectiveness in reducing rhinosinusitis symptoms, performing large-volume, low-pressure nasal saline irrigation is not intuitive—and may sound downright scary to some patients. The need to learn how to perform nasal irrigation effectively, overcome the fear of water in the nasal cavity, and find the time to perform irrigation regularly can be barriers to this treatment.

A little bit of coaching can go a long way

A study by Rabago et al¹⁶ found that coached practice and patient education are effective tools in mastery of the technique ( PATIENT HANDOUT ).^10,17 The researchers also found that several home strategies—incorporating nasal irrigation into the daily hygiene routine, placing the materials in a convenient location, and using warm water—facilitate regular use.

There is evidence, too, that patients who successfully use large-volume, low-pressure saline irrigation gain more than symptom relief. Rabago et al also found that effective use of this technique was associated with a sense of empowerment, and led to improved self-management skills, as well as a rapid, and long-term, improvement in quality of life.¹⁶

PATIENT HANDOUT

Saline nasal irrigation Your step-by-step guide

STEP 1: GATHER THE SUPPLIES

• - Salt (kosher, canning, or pickling salt)
• - Baking soda
• - Nasal irrigation pot (available at most pharmacies)
• - Measuring spoons
• - Container with lid

OR

• - An irrigation kit that includes the device and premixed saline packets

STEP 2: PREPARE THE SOLUTION

• - Put 1 tsp salt and ½ tsp baking soda into the container.
• - Add 1 pint of lukewarm tap water.
• - Mix contents.
• - Fill the nasal pot.

STEP 3: POSITION YOUR HEAD

• - Lean over the sink; rotate your head to one side.
• - Insert the spout of the irrigation device into the uppermost nostril.
• - Breathe through your mouth.
• - Raise the handle of the nasal pot so the solution flows into the upper nostril; in a few moments, the solution will begin to drain from the lower nostril.
• - Continue until the pot is empty, then exhale gently through both nostrils and gently blow your nose.
• - Refill the nasal pot, turn your head to the opposite side, and repeat with the other nostril.
• - Do this twice a day or as directed.

STEP 4: CLEAN AND PUT AWAY THE EQUIPMENT

• - Wash the nasal pot daily with warm water and dish detergent; rinse thoroughly.
• - Store unused saline solution in the sealed container; it can be kept at room temperature and reused for 2 days.

Adapted from: University of Wisconsin Department of Family Medicine.¹⁷

Acknowledgement

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

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 45-year-old woman presents to your office with an 8-month history of nasal congestion and thick nasal discharge. Her symptoms have waxed and waned, the patient reports. She’s tried decongestants, antibiotics, and nasal steroids, with limited success. The patient has not had a recent respiratory infection, has never had sinus surgery, and does not want to be on long-term medication. You wonder if there’s an alternative treatment you can offer.

Rhinosinusitis is one of the most common conditions seen by primary care physicians in the United States, and its incidence and prevalence are increasing.^2,3 While acute rhinosinusitis is usually self-limiting and resolves within a month, some patients develop chronic—and hard to treat—sinonasal symptoms.

No single cause, no definitive treatment

We’ve moved away from the notion that chronic rhinosinusitis is always a manifestation of persistent bacterial infection, and now recognize that there’s an inflammatory, nonbacterial component.⁴ In any given patient, several mechanisms—acting either simultaneously or independently—may contribute to sinonasal symptoms.³

Chronic sinusitis is treated in a variety of ways, including medications, immunotherapy, and surgery. Despite their limited efficacy, antibiotics and nasal steroids have been the mainstays of treatment.⁵ Treating underlying allergies, when they exist, may be helpful. But regardless of which treatment patients receive for chronic rhinosinusitis, many remain symptomatic.⁶

Benefits of saline irrigation extend beyond postop care

Otolaryngologists recommend saline irrigation after sinus surgery to clear secretions, debris, and crusts; reduce the risk of postoperative mucosal adhesions; and expedite mucosal healing.^7,8 Saline irrigation is also gaining popularity as an alternative approach to chronic sinusitis symptom relief, and several randomized controlled trials (RCTs) have demonstrated both objective and subjective efficacy of this treatment for sinonasal disease.^8-11

In 2007, the Cochrane Collaboration reviewed evidence for the effectiveness of nasal saline irrigation for symptoms of chronic rhinosinusitis. The reviewers concluded that it is well tolerated and beneficial, whether used alone or as an adjunctive treatment.¹²

Nasal saline sprays are often recommended because they’re thought to be better tolerated than other delivery modes.¹³ There have, however, been no comparisons of the relative efficacy of different means of saline delivery, until now.

STUDY SUMMARY: Nasal irrigation and spray go head-to-head

This study was a high-quality, prospective RCT comparing nasal spray and nasal irrigation.¹ Subjects were recruited from the general population. To be eligible, participants had to be 18 years of age or older and have reported at least one of the following chronic rhinosinusitis symptoms on 4 or more days each week in the preceding 2 weeks:

• nasal stuffiness
• nasal dryness or crusting
• nasal congestion
• thick or discolored nasal discharge.

In addition, the symptoms must have been present on at least 15 of the preceding 30 days. Exclusion criteria included recent sinus surgery, a respiratory infection within the past 2 weeks, and the use of nasal saline within the past month.

Researchers enrolled 127 patients in the study; 63 were randomized to the nasal spray group and 64 to the large-volume, low-pressure irrigation group. Demographic and baseline characteristics of the groups were similar. The average ages of those in the irrigation and spray groups were 45 and 48 years, respectively. Most patients were nonsmokers and had been symptomatic for 7 to 12 months.

Twice-daily treatment. Researchers asked the patients to perform the assigned treatment twice daily for 8 weeks, but the patients were also permitted to continue using their usual medications. Symptom severity and disease-specific quality of life were assessed with the Sino-Nasal Outcome Test (SNOT-20), a 20-item survey that measures physical problems, emotional consequences, and functional limitations of sinusitis.¹⁴

The SNOT-20 is a validated, self-administered survey that asks patients to score items such as runny nose, postnasal discharge, need to blow the nose, reduced productivity, and embarrassment, on a 0- to 5-point scale (0=never, 5=always). A SNOT-20 score of 100 indicates the worst possible symptoms.

As a measure of chronicity of symptoms, patients were also asked to estimate how many months they’d had these symptoms during the last year. In addition, they were instructed to keep a diary to document treatment compliance and the use of other medications for sinonasal symptoms.

To measure outcomes, the researchers provided patients with mail-in packets so they could send in their completed SNOT-20 questionnaire and the medication diary completed at 2, 4, and 8 weeks after randomization.

Biggest improvements seen in irrigation group

Severity of symptoms. In each outcome measurement period, the saline irrigation group had lower SNOT-20 scores than the nasal spray group. At 2 weeks, the irrigation group scores were 4.4 points lower than the spray group (P=.02); at 4 weeks, the scores were 8.2 points lower (P<.001), and at 8 weeks the scores were 6.4 points lower (P=.002). Those in the irrigation group also had a significantly greater change from baseline than the patients in the spray group at 4 weeks (16.2 vs 7.4, P=.002) and at 8 weeks (15.0 vs 8.5, P=.04). The difference was marginally significant at 2 weeks (12.2 vs 6.7, P=.05).

Frequency of symptoms. At 8 weeks, 40% of the irrigation group and 61% of the nasal spray group reported nasal or sinus symptoms “often or always.” The absolute risk reduction in symptom frequency with saline irrigations, therefore, was 0.21; 95% confidence interval, 0.02-0.38 (P=.01). The odds of frequent nasal symptoms were 50% lower in the irrigation group compared to the spray group.

WHAT’S NEW: One delivery method is better than another

Prior studies had proven the effectiveness of nasal saline for reduction of rhinosinusitis symptoms. This RCT demonstrated that large-volume, low-pressure nasal irrigation brings greater symptom relief than nasal spray.

The researchers found little difference between the 2 groups in the rate of adverse effects, and reported that nasal irrigation appears to be well accepted once patients become accustomed to it. The fact that the participants were recruited from the general population further suggests that the results will be generalizable to primary care patients.

CAVEATS: High dropout rate in irrigation group

The absence of a control group prevents us from knowing the effect of saline nasal spray or irrigation compared with no treatment. In prior studies, however, nasal saline spray was found to be more effective than placebo in reducing rhinosinusitis symptoms.^8,15

It is notable that a significant portion (21%) of the irrigation group abandoned this treatment by 8 weeks; in comparison, just 7% of the nasal spray group discontinued treatment.

This lower rate of adherence makes the beneficial effects of the irrigation group even more impressive. But it also suggests that a significant portion of patients are unlikely to stay with this recommended regimen. For those who try saline irrigation and choose not to continue it or are unwilling even to try it, saline spray is a reasonable alternative.

It should be noted that financial support for this study was provided by NeilMed Pharmaceuticals, a manufacturer of nasal saline solution and irrigation devices. However, the sponsor was not involved in the design or conduct of the study, in data collection or analysis, or in the preparation of the manuscript.

CHALLENGES TO IMPLEMENTATION: Tx may “scare away” some patients

Despite its effectiveness in reducing rhinosinusitis symptoms, performing large-volume, low-pressure nasal saline irrigation is not intuitive—and may sound downright scary to some patients. The need to learn how to perform nasal irrigation effectively, overcome the fear of water in the nasal cavity, and find the time to perform irrigation regularly can be barriers to this treatment.

A little bit of coaching can go a long way

A study by Rabago et al¹⁶ found that coached practice and patient education are effective tools in mastery of the technique ( PATIENT HANDOUT ).^10,17 The researchers also found that several home strategies—incorporating nasal irrigation into the daily hygiene routine, placing the materials in a convenient location, and using warm water—facilitate regular use.

There is evidence, too, that patients who successfully use large-volume, low-pressure saline irrigation gain more than symptom relief. Rabago et al also found that effective use of this technique was associated with a sense of empowerment, and led to improved self-management skills, as well as a rapid, and long-term, improvement in quality of life.¹⁶

PATIENT HANDOUT

Saline nasal irrigation Your step-by-step guide

STEP 1: GATHER THE SUPPLIES

• - Salt (kosher, canning, or pickling salt)
• - Baking soda
• - Nasal irrigation pot (available at most pharmacies)
• - Measuring spoons
• - Container with lid

OR

• - An irrigation kit that includes the device and premixed saline packets

STEP 2: PREPARE THE SOLUTION

• - Put 1 tsp salt and ½ tsp baking soda into the container.
• - Add 1 pint of lukewarm tap water.
• - Mix contents.
• - Fill the nasal pot.

STEP 3: POSITION YOUR HEAD

• - Lean over the sink; rotate your head to one side.
• - Insert the spout of the irrigation device into the uppermost nostril.
• - Breathe through your mouth.
• - Raise the handle of the nasal pot so the solution flows into the upper nostril; in a few moments, the solution will begin to drain from the lower nostril.
• - Continue until the pot is empty, then exhale gently through both nostrils and gently blow your nose.
• - Refill the nasal pot, turn your head to the opposite side, and repeat with the other nostril.
• - Do this twice a day or as directed.

STEP 4: CLEAN AND PUT AWAY THE EQUIPMENT

• - Wash the nasal pot daily with warm water and dish detergent; rinse thoroughly.
• - Store unused saline solution in the sealed container; it can be kept at room temperature and reused for 2 days.

Adapted from: University of Wisconsin Department of Family Medicine.¹⁷

Acknowledgement

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

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

Click here to view PURL METHODOLOGY

ILLUSTRATIVE CASE

A 45-year-old woman presents to your office with an 8-month history of nasal congestion and thick nasal discharge. Her symptoms have waxed and waned, the patient reports. She’s tried decongestants, antibiotics, and nasal steroids, with limited success. The patient has not had a recent respiratory infection, has never had sinus surgery, and does not want to be on long-term medication. You wonder if there’s an alternative treatment you can offer.

Rhinosinusitis is one of the most common conditions seen by primary care physicians in the United States, and its incidence and prevalence are increasing.^2,3 While acute rhinosinusitis is usually self-limiting and resolves within a month, some patients develop chronic—and hard to treat—sinonasal symptoms.

No single cause, no definitive treatment

We’ve moved away from the notion that chronic rhinosinusitis is always a manifestation of persistent bacterial infection, and now recognize that there’s an inflammatory, nonbacterial component.⁴ In any given patient, several mechanisms—acting either simultaneously or independently—may contribute to sinonasal symptoms.³

Chronic sinusitis is treated in a variety of ways, including medications, immunotherapy, and surgery. Despite their limited efficacy, antibiotics and nasal steroids have been the mainstays of treatment.⁵ Treating underlying allergies, when they exist, may be helpful. But regardless of which treatment patients receive for chronic rhinosinusitis, many remain symptomatic.⁶

Benefits of saline irrigation extend beyond postop care

Otolaryngologists recommend saline irrigation after sinus surgery to clear secretions, debris, and crusts; reduce the risk of postoperative mucosal adhesions; and expedite mucosal healing.^7,8 Saline irrigation is also gaining popularity as an alternative approach to chronic sinusitis symptom relief, and several randomized controlled trials (RCTs) have demonstrated both objective and subjective efficacy of this treatment for sinonasal disease.^8-11

In 2007, the Cochrane Collaboration reviewed evidence for the effectiveness of nasal saline irrigation for symptoms of chronic rhinosinusitis. The reviewers concluded that it is well tolerated and beneficial, whether used alone or as an adjunctive treatment.¹²

Nasal saline sprays are often recommended because they’re thought to be better tolerated than other delivery modes.¹³ There have, however, been no comparisons of the relative efficacy of different means of saline delivery, until now.

STUDY SUMMARY: Nasal irrigation and spray go head-to-head

This study was a high-quality, prospective RCT comparing nasal spray and nasal irrigation.¹ Subjects were recruited from the general population. To be eligible, participants had to be 18 years of age or older and have reported at least one of the following chronic rhinosinusitis symptoms on 4 or more days each week in the preceding 2 weeks:

• nasal stuffiness
• nasal dryness or crusting
• nasal congestion
• thick or discolored nasal discharge.

In addition, the symptoms must have been present on at least 15 of the preceding 30 days. Exclusion criteria included recent sinus surgery, a respiratory infection within the past 2 weeks, and the use of nasal saline within the past month.

Researchers enrolled 127 patients in the study; 63 were randomized to the nasal spray group and 64 to the large-volume, low-pressure irrigation group. Demographic and baseline characteristics of the groups were similar. The average ages of those in the irrigation and spray groups were 45 and 48 years, respectively. Most patients were nonsmokers and had been symptomatic for 7 to 12 months.

Twice-daily treatment. Researchers asked the patients to perform the assigned treatment twice daily for 8 weeks, but the patients were also permitted to continue using their usual medications. Symptom severity and disease-specific quality of life were assessed with the Sino-Nasal Outcome Test (SNOT-20), a 20-item survey that measures physical problems, emotional consequences, and functional limitations of sinusitis.¹⁴

The SNOT-20 is a validated, self-administered survey that asks patients to score items such as runny nose, postnasal discharge, need to blow the nose, reduced productivity, and embarrassment, on a 0- to 5-point scale (0=never, 5=always). A SNOT-20 score of 100 indicates the worst possible symptoms.

As a measure of chronicity of symptoms, patients were also asked to estimate how many months they’d had these symptoms during the last year. In addition, they were instructed to keep a diary to document treatment compliance and the use of other medications for sinonasal symptoms.

To measure outcomes, the researchers provided patients with mail-in packets so they could send in their completed SNOT-20 questionnaire and the medication diary completed at 2, 4, and 8 weeks after randomization.

Biggest improvements seen in irrigation group

Severity of symptoms. In each outcome measurement period, the saline irrigation group had lower SNOT-20 scores than the nasal spray group. At 2 weeks, the irrigation group scores were 4.4 points lower than the spray group (P=.02); at 4 weeks, the scores were 8.2 points lower (P<.001), and at 8 weeks the scores were 6.4 points lower (P=.002). Those in the irrigation group also had a significantly greater change from baseline than the patients in the spray group at 4 weeks (16.2 vs 7.4, P=.002) and at 8 weeks (15.0 vs 8.5, P=.04). The difference was marginally significant at 2 weeks (12.2 vs 6.7, P=.05).

Frequency of symptoms. At 8 weeks, 40% of the irrigation group and 61% of the nasal spray group reported nasal or sinus symptoms “often or always.” The absolute risk reduction in symptom frequency with saline irrigations, therefore, was 0.21; 95% confidence interval, 0.02-0.38 (P=.01). The odds of frequent nasal symptoms were 50% lower in the irrigation group compared to the spray group.

WHAT’S NEW: One delivery method is better than another

Prior studies had proven the effectiveness of nasal saline for reduction of rhinosinusitis symptoms. This RCT demonstrated that large-volume, low-pressure nasal irrigation brings greater symptom relief than nasal spray.

The researchers found little difference between the 2 groups in the rate of adverse effects, and reported that nasal irrigation appears to be well accepted once patients become accustomed to it. The fact that the participants were recruited from the general population further suggests that the results will be generalizable to primary care patients.

CAVEATS: High dropout rate in irrigation group

The absence of a control group prevents us from knowing the effect of saline nasal spray or irrigation compared with no treatment. In prior studies, however, nasal saline spray was found to be more effective than placebo in reducing rhinosinusitis symptoms.^8,15

It is notable that a significant portion (21%) of the irrigation group abandoned this treatment by 8 weeks; in comparison, just 7% of the nasal spray group discontinued treatment.

This lower rate of adherence makes the beneficial effects of the irrigation group even more impressive. But it also suggests that a significant portion of patients are unlikely to stay with this recommended regimen. For those who try saline irrigation and choose not to continue it or are unwilling even to try it, saline spray is a reasonable alternative.

It should be noted that financial support for this study was provided by NeilMed Pharmaceuticals, a manufacturer of nasal saline solution and irrigation devices. However, the sponsor was not involved in the design or conduct of the study, in data collection or analysis, or in the preparation of the manuscript.

CHALLENGES TO IMPLEMENTATION: Tx may “scare away” some patients

Despite its effectiveness in reducing rhinosinusitis symptoms, performing large-volume, low-pressure nasal saline irrigation is not intuitive—and may sound downright scary to some patients. The need to learn how to perform nasal irrigation effectively, overcome the fear of water in the nasal cavity, and find the time to perform irrigation regularly can be barriers to this treatment.

A little bit of coaching can go a long way

A study by Rabago et al¹⁶ found that coached practice and patient education are effective tools in mastery of the technique ( PATIENT HANDOUT ).^10,17 The researchers also found that several home strategies—incorporating nasal irrigation into the daily hygiene routine, placing the materials in a convenient location, and using warm water—facilitate regular use.

There is evidence, too, that patients who successfully use large-volume, low-pressure saline irrigation gain more than symptom relief. Rabago et al also found that effective use of this technique was associated with a sense of empowerment, and led to improved self-management skills, as well as a rapid, and long-term, improvement in quality of life.¹⁶

PATIENT HANDOUT

Saline nasal irrigation Your step-by-step guide

STEP 1: GATHER THE SUPPLIES

• - Salt (kosher, canning, or pickling salt)
• - Baking soda
• - Nasal irrigation pot (available at most pharmacies)
• - Measuring spoons
• - Container with lid

OR

• - An irrigation kit that includes the device and premixed saline packets

STEP 2: PREPARE THE SOLUTION

• - Put 1 tsp salt and ½ tsp baking soda into the container.
• - Add 1 pint of lukewarm tap water.
• - Mix contents.
• - Fill the nasal pot.

STEP 3: POSITION YOUR HEAD

• - Lean over the sink; rotate your head to one side.
• - Insert the spout of the irrigation device into the uppermost nostril.
• - Breathe through your mouth.
• - Raise the handle of the nasal pot so the solution flows into the upper nostril; in a few moments, the solution will begin to drain from the lower nostril.
• - Continue until the pot is empty, then exhale gently through both nostrils and gently blow your nose.
• - Refill the nasal pot, turn your head to the opposite side, and repeat with the other nostril.
• - Do this twice a day or as directed.

STEP 4: CLEAN AND PUT AWAY THE EQUIPMENT

• - Wash the nasal pot daily with warm water and dish detergent; rinse thoroughly.
• - Store unused saline solution in the sealed container; it can be kept at room temperature and reused for 2 days.

Adapted from: University of Wisconsin Department of Family Medicine.¹⁷

Acknowledgement

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

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

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