Debra Stulberg, MD, MA

Illustrative case

A 10-year-old boy comes in with his mother for a well-child check-up. His BMI is 40 kg/m²—above the 99th percentile for his age and up from 37 a year ago. His blood pressure is 120/84 mm Hg. What treatment, if any, should you offer for his obesity?

Childhood obesity is a global epidemic. In the United States, 19.6% of children ages 6 through 11 and 18.1% of 12- to 19-year-olds are obese, a 3-fold increase in the last 30 years.³ Without intervention, most obese adolescents will become obese adults, threatening to reverse the progress in slowing cardiovascular morbidity and mortality that has occurred over the past few decades.³

Obese kids get adult diseases
Obesity is a risk factor for a variety of chronic conditions, including cardiovascular disease, cerebrovascular disease, and arthritis. Severe obesity is also associated with higher mortality rates.⁴ Unfortunately, these comorbidities are not limited to adulthood.

“Adult” diseases, such as obstructive sleep apnea, dyslipidemia, and type 2 diabetes, are increasingly seen in children and adolescents.¹ Nutritional deficits such as vitamin D and iron deficiency are often seen in obese children, as well.⁵ There are also psychological ramifications of childhood obesity, including social isolation and depression.⁶

The USPSTF recently upgraded its recommendation regarding obesity screening in children ages 6 and older from I (insufficient evidence) to B (a positive grade based on high or moderate certainty of the benefit of the intervention), citing new evidence in favor of screening and treating or referring children when appropriate.² The systematic review we report on here, which formed the basis for the USPSTF’s upgrade, focused on management options for children identified as overweight or obese.

STUDY SUMMARY: Intense, comprehensive efforts pay off

This systematic review¹ included studies of children ages 4 to 18 years who were overweight (defined as a body mass index [BMI] in the 85th to 94th percentile for age and sex) or obese (either a BMI at or above the 95th percentile for age and sex or a BMI >30 kg/m²). The researchers found 25 trials—15 of behavioral interventions alone and 10 that combined behavioral and pharmacologic interventions—that met their criteria: The studies focused on weight loss and/or maintenance, reported outcomes ≥6 months from baseline, and were conducted (or feasible) in a primary care setting.

Behavioral interventions were categorized by treatment intensity (as measured by hours of contact, which ranged from <10 hours to >75) and comprehensiveness (including nutritional counseling, physical activity counseling or participation, and counseling on behavioral management techniques). Weight outcomes were categorized as short-term (6-12 months since treatment initiation) or maintenance (≥12 months after the end of active treatment).

The 15 behavioral intervention trials included 1258 children ages 4 to 18 years, most of whom were obese. Most trials were small and reported high retention rates. All had beneficial effects on weight in the intervention group compared with the controls, but not all changes were statistically significant. Higher intensity and more comprehensive programs had better outcomes.

The largest effects were in 3 moderate- to high-intensity, comprehensive weight management programs with ≥26 hours of contact. These 3 trials demonstrated a difference in BMI of 1.9 to 3.3 in the intervention groups at 12 months compared with the controls. (A 3.3 difference in BMI is equal to approximately 13 lb in an 8-year-old and 17 lb in a 12-year-old.)

Four behavioral intervention studies reported outcomes ≥12 months after completing the intervention (range 15-48 months). Three of the 4 reported continued beneficial effects on weight after the active treatment period, but the effects were markedly attenuated.

The only adverse effect reported in the trials of behavioral interventions was the injury rate among children in an exercise program, but it was minimal: One fracture was reported, vs no injuries for the controls. No differences were reported in height, eating disorders, or depression. However, fewer than half of the behavioral intervention trials reported on adverse effects.

Weight loss drugs have modest effects
Ten trials combining pharmacologic and behavioral interventions involved a total of 1294 obese adolescents ages 12 to 19. All evaluated short-term weight loss effects of either sibutramine (10-15 mg/d) or orlistat (120 mg tid). Trials ranged from 3 to 12 months. Participants in both the control and intervention groups received behavioral counseling.

The trials all favored the treatment groups, although not all of the results were statistically significant. Trials of longer duration (12 months) had more favorable results than those lasting 6 months.

The largest sibutramine trial (n=498) reported a mean BMI reduction of 2.9 in the treatment group, compared with a reduction of 0.3 in the control group (P<.001). This corresponds to an average weight loss of 14 lb in the intervention group, vs 4.2 lb in the control group, after 12 months.

The largest orlistat trial (n=539) reported a mean BMI reduction in the treatment group of 0.6, vs 0.3 in the control group (P<.001)—an average weight loss of 4.2 lb in the intervention group, compared with 2.1 lb among the controls after 12 months. None of the trials evaluated weight change after cessation of the study drug, and none compared orlistat with sibutramine.

Adverse effects in the sibutramine-treated patients were primarily cardiovascular and gastrointestinal. Cardiovascular effects included tachycardia and increases in systolic and diastolic blood pressure. The differences between the intervention and control groups were small, and no differences were observed in discontinuation rates caused by adverse events. Nor were differences reported in growth and maturation between the intervention and control groups.

Adverse effects in the orlistat-treated patients were also low and similar in the intervention and control groups. Gastrointestinal effects were common. The number needed to harm (NNH) for fatty or oily stools was 2,⁴ and the NNH for fecal incontinence was 12.⁵

WHAT'S NEW: Clinicians treating obese kids have cause for optimism

Although the trials included in this review were heterogeneous and many were small, this systematic review provides evidence that intensive, comprehensive behavioral weight loss interventions for obese children can be effective up to 12 months after the conclusion of the program. Family physicians should consider referring obese children and adolescents to such programs—or finding ways to provide supportive strategies themselves.

Sibutramine and orlistat may be helpful in the context of comprehensive, intensive behavioral interventions, although there is no follow-up data to demonstrate long-term safety and weight maintenance after the medication is stopped.

CAVEATS: Little is known about long-term safety of the drugs

There have been few randomized trials of pharmacologic interventions in adolescents and none evaluating weight maintenance after 12 months (or discontinuation of treatment), or assessing long-term safety of the medication.

Sibutramine is not approved by the US Food and Drug Administration (FDA) for use in children or adolescents.⁷ Orlistat is currently approved only for individuals over the age of 12.⁸

In January 2010, an additional contraindication was added to the sibutramine drug label, stating that it is not to be used in patients with a history of cardiovascular disease.⁹ And the FDA is currently investigating a rare association between orlistat and liver injury, although no conclusions have been released.¹⁰ Children and adolescents are particularly vulnerable to long-term side effects, given their relatively young age at the time of drug initiation, so we urge caution with the use of these drugs in this patient population.

CHALLENGES TO IMPLEMENTATION: Intensive approach may be hard to reproduce

Implementation of high-intensity comprehensive interventions for obese children faces a number of roadblocks, including limited availability of programs, cost, and reimbursement. Most of the intensive interventions in these trials took place in specialty centers rather than in primary care offices. Replicating them could require a referral—or significant resources within the primary care setting itself. Yet many, if not most, insurance policies still do not cover such extensive lifestyle interventions. (For information on weight loss interventions for adults, see “Weight loss strategies that really work”).

None of these trials reported on cost or cost effectiveness. Despite the considerable cost of a comprehensive obesity management program, however, a successful weight-maintenance model could be a worthwhile investment in long-term health.

Lastly, the results of this trial should not negate the importance of obesity prevention efforts by parents, who are in the best position to reverse the childhood obesity epidemic.¹¹

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999; awarded by the National Center for Research Resources; the grant is 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 10-year-old boy comes in with his mother for a well-child check-up. His BMI is 40 kg/m²—above the 99th percentile for his age and up from 37 a year ago. His blood pressure is 120/84 mm Hg. What treatment, if any, should you offer for his obesity?

Childhood obesity is a global epidemic. In the United States, 19.6% of children ages 6 through 11 and 18.1% of 12- to 19-year-olds are obese, a 3-fold increase in the last 30 years.³ Without intervention, most obese adolescents will become obese adults, threatening to reverse the progress in slowing cardiovascular morbidity and mortality that has occurred over the past few decades.³

Obese kids get adult diseases
Obesity is a risk factor for a variety of chronic conditions, including cardiovascular disease, cerebrovascular disease, and arthritis. Severe obesity is also associated with higher mortality rates.⁴ Unfortunately, these comorbidities are not limited to adulthood.

“Adult” diseases, such as obstructive sleep apnea, dyslipidemia, and type 2 diabetes, are increasingly seen in children and adolescents.¹ Nutritional deficits such as vitamin D and iron deficiency are often seen in obese children, as well.⁵ There are also psychological ramifications of childhood obesity, including social isolation and depression.⁶

The USPSTF recently upgraded its recommendation regarding obesity screening in children ages 6 and older from I (insufficient evidence) to B (a positive grade based on high or moderate certainty of the benefit of the intervention), citing new evidence in favor of screening and treating or referring children when appropriate.² The systematic review we report on here, which formed the basis for the USPSTF’s upgrade, focused on management options for children identified as overweight or obese.

STUDY SUMMARY: Intense, comprehensive efforts pay off

This systematic review¹ included studies of children ages 4 to 18 years who were overweight (defined as a body mass index [BMI] in the 85th to 94th percentile for age and sex) or obese (either a BMI at or above the 95th percentile for age and sex or a BMI >30 kg/m²). The researchers found 25 trials—15 of behavioral interventions alone and 10 that combined behavioral and pharmacologic interventions—that met their criteria: The studies focused on weight loss and/or maintenance, reported outcomes ≥6 months from baseline, and were conducted (or feasible) in a primary care setting.

Behavioral interventions were categorized by treatment intensity (as measured by hours of contact, which ranged from <10 hours to >75) and comprehensiveness (including nutritional counseling, physical activity counseling or participation, and counseling on behavioral management techniques). Weight outcomes were categorized as short-term (6-12 months since treatment initiation) or maintenance (≥12 months after the end of active treatment).

The 15 behavioral intervention trials included 1258 children ages 4 to 18 years, most of whom were obese. Most trials were small and reported high retention rates. All had beneficial effects on weight in the intervention group compared with the controls, but not all changes were statistically significant. Higher intensity and more comprehensive programs had better outcomes.

The largest effects were in 3 moderate- to high-intensity, comprehensive weight management programs with ≥26 hours of contact. These 3 trials demonstrated a difference in BMI of 1.9 to 3.3 in the intervention groups at 12 months compared with the controls. (A 3.3 difference in BMI is equal to approximately 13 lb in an 8-year-old and 17 lb in a 12-year-old.)

Four behavioral intervention studies reported outcomes ≥12 months after completing the intervention (range 15-48 months). Three of the 4 reported continued beneficial effects on weight after the active treatment period, but the effects were markedly attenuated.

The only adverse effect reported in the trials of behavioral interventions was the injury rate among children in an exercise program, but it was minimal: One fracture was reported, vs no injuries for the controls. No differences were reported in height, eating disorders, or depression. However, fewer than half of the behavioral intervention trials reported on adverse effects.

Weight loss drugs have modest effects
Ten trials combining pharmacologic and behavioral interventions involved a total of 1294 obese adolescents ages 12 to 19. All evaluated short-term weight loss effects of either sibutramine (10-15 mg/d) or orlistat (120 mg tid). Trials ranged from 3 to 12 months. Participants in both the control and intervention groups received behavioral counseling.

The trials all favored the treatment groups, although not all of the results were statistically significant. Trials of longer duration (12 months) had more favorable results than those lasting 6 months.

The largest sibutramine trial (n=498) reported a mean BMI reduction of 2.9 in the treatment group, compared with a reduction of 0.3 in the control group (P<.001). This corresponds to an average weight loss of 14 lb in the intervention group, vs 4.2 lb in the control group, after 12 months.

The largest orlistat trial (n=539) reported a mean BMI reduction in the treatment group of 0.6, vs 0.3 in the control group (P<.001)—an average weight loss of 4.2 lb in the intervention group, compared with 2.1 lb among the controls after 12 months. None of the trials evaluated weight change after cessation of the study drug, and none compared orlistat with sibutramine.

Adverse effects in the sibutramine-treated patients were primarily cardiovascular and gastrointestinal. Cardiovascular effects included tachycardia and increases in systolic and diastolic blood pressure. The differences between the intervention and control groups were small, and no differences were observed in discontinuation rates caused by adverse events. Nor were differences reported in growth and maturation between the intervention and control groups.

Adverse effects in the orlistat-treated patients were also low and similar in the intervention and control groups. Gastrointestinal effects were common. The number needed to harm (NNH) for fatty or oily stools was 2,⁴ and the NNH for fecal incontinence was 12.⁵

WHAT'S NEW: Clinicians treating obese kids have cause for optimism

Although the trials included in this review were heterogeneous and many were small, this systematic review provides evidence that intensive, comprehensive behavioral weight loss interventions for obese children can be effective up to 12 months after the conclusion of the program. Family physicians should consider referring obese children and adolescents to such programs—or finding ways to provide supportive strategies themselves.

Sibutramine and orlistat may be helpful in the context of comprehensive, intensive behavioral interventions, although there is no follow-up data to demonstrate long-term safety and weight maintenance after the medication is stopped.

CAVEATS: Little is known about long-term safety of the drugs

There have been few randomized trials of pharmacologic interventions in adolescents and none evaluating weight maintenance after 12 months (or discontinuation of treatment), or assessing long-term safety of the medication.

Sibutramine is not approved by the US Food and Drug Administration (FDA) for use in children or adolescents.⁷ Orlistat is currently approved only for individuals over the age of 12.⁸

In January 2010, an additional contraindication was added to the sibutramine drug label, stating that it is not to be used in patients with a history of cardiovascular disease.⁹ And the FDA is currently investigating a rare association between orlistat and liver injury, although no conclusions have been released.¹⁰ Children and adolescents are particularly vulnerable to long-term side effects, given their relatively young age at the time of drug initiation, so we urge caution with the use of these drugs in this patient population.

CHALLENGES TO IMPLEMENTATION: Intensive approach may be hard to reproduce

Implementation of high-intensity comprehensive interventions for obese children faces a number of roadblocks, including limited availability of programs, cost, and reimbursement. Most of the intensive interventions in these trials took place in specialty centers rather than in primary care offices. Replicating them could require a referral—or significant resources within the primary care setting itself. Yet many, if not most, insurance policies still do not cover such extensive lifestyle interventions. (For information on weight loss interventions for adults, see “Weight loss strategies that really work”).

None of these trials reported on cost or cost effectiveness. Despite the considerable cost of a comprehensive obesity management program, however, a successful weight-maintenance model could be a worthwhile investment in long-term health.

Lastly, the results of this trial should not negate the importance of obesity prevention efforts by parents, who are in the best position to reverse the childhood obesity epidemic.¹¹

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999; awarded by the National Center for Research Resources; the grant is 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 10-year-old boy comes in with his mother for a well-child check-up. His BMI is 40 kg/m²—above the 99th percentile for his age and up from 37 a year ago. His blood pressure is 120/84 mm Hg. What treatment, if any, should you offer for his obesity?

Childhood obesity is a global epidemic. In the United States, 19.6% of children ages 6 through 11 and 18.1% of 12- to 19-year-olds are obese, a 3-fold increase in the last 30 years.³ Without intervention, most obese adolescents will become obese adults, threatening to reverse the progress in slowing cardiovascular morbidity and mortality that has occurred over the past few decades.³

Obese kids get adult diseases
Obesity is a risk factor for a variety of chronic conditions, including cardiovascular disease, cerebrovascular disease, and arthritis. Severe obesity is also associated with higher mortality rates.⁴ Unfortunately, these comorbidities are not limited to adulthood.

“Adult” diseases, such as obstructive sleep apnea, dyslipidemia, and type 2 diabetes, are increasingly seen in children and adolescents.¹ Nutritional deficits such as vitamin D and iron deficiency are often seen in obese children, as well.⁵ There are also psychological ramifications of childhood obesity, including social isolation and depression.⁶

The USPSTF recently upgraded its recommendation regarding obesity screening in children ages 6 and older from I (insufficient evidence) to B (a positive grade based on high or moderate certainty of the benefit of the intervention), citing new evidence in favor of screening and treating or referring children when appropriate.² The systematic review we report on here, which formed the basis for the USPSTF’s upgrade, focused on management options for children identified as overweight or obese.

STUDY SUMMARY: Intense, comprehensive efforts pay off

This systematic review¹ included studies of children ages 4 to 18 years who were overweight (defined as a body mass index [BMI] in the 85th to 94th percentile for age and sex) or obese (either a BMI at or above the 95th percentile for age and sex or a BMI >30 kg/m²). The researchers found 25 trials—15 of behavioral interventions alone and 10 that combined behavioral and pharmacologic interventions—that met their criteria: The studies focused on weight loss and/or maintenance, reported outcomes ≥6 months from baseline, and were conducted (or feasible) in a primary care setting.

Behavioral interventions were categorized by treatment intensity (as measured by hours of contact, which ranged from <10 hours to >75) and comprehensiveness (including nutritional counseling, physical activity counseling or participation, and counseling on behavioral management techniques). Weight outcomes were categorized as short-term (6-12 months since treatment initiation) or maintenance (≥12 months after the end of active treatment).

The 15 behavioral intervention trials included 1258 children ages 4 to 18 years, most of whom were obese. Most trials were small and reported high retention rates. All had beneficial effects on weight in the intervention group compared with the controls, but not all changes were statistically significant. Higher intensity and more comprehensive programs had better outcomes.

The largest effects were in 3 moderate- to high-intensity, comprehensive weight management programs with ≥26 hours of contact. These 3 trials demonstrated a difference in BMI of 1.9 to 3.3 in the intervention groups at 12 months compared with the controls. (A 3.3 difference in BMI is equal to approximately 13 lb in an 8-year-old and 17 lb in a 12-year-old.)

Four behavioral intervention studies reported outcomes ≥12 months after completing the intervention (range 15-48 months). Three of the 4 reported continued beneficial effects on weight after the active treatment period, but the effects were markedly attenuated.

The only adverse effect reported in the trials of behavioral interventions was the injury rate among children in an exercise program, but it was minimal: One fracture was reported, vs no injuries for the controls. No differences were reported in height, eating disorders, or depression. However, fewer than half of the behavioral intervention trials reported on adverse effects.

Weight loss drugs have modest effects
Ten trials combining pharmacologic and behavioral interventions involved a total of 1294 obese adolescents ages 12 to 19. All evaluated short-term weight loss effects of either sibutramine (10-15 mg/d) or orlistat (120 mg tid). Trials ranged from 3 to 12 months. Participants in both the control and intervention groups received behavioral counseling.

The trials all favored the treatment groups, although not all of the results were statistically significant. Trials of longer duration (12 months) had more favorable results than those lasting 6 months.

The largest sibutramine trial (n=498) reported a mean BMI reduction of 2.9 in the treatment group, compared with a reduction of 0.3 in the control group (P<.001). This corresponds to an average weight loss of 14 lb in the intervention group, vs 4.2 lb in the control group, after 12 months.

The largest orlistat trial (n=539) reported a mean BMI reduction in the treatment group of 0.6, vs 0.3 in the control group (P<.001)—an average weight loss of 4.2 lb in the intervention group, compared with 2.1 lb among the controls after 12 months. None of the trials evaluated weight change after cessation of the study drug, and none compared orlistat with sibutramine.

Adverse effects in the sibutramine-treated patients were primarily cardiovascular and gastrointestinal. Cardiovascular effects included tachycardia and increases in systolic and diastolic blood pressure. The differences between the intervention and control groups were small, and no differences were observed in discontinuation rates caused by adverse events. Nor were differences reported in growth and maturation between the intervention and control groups.

Adverse effects in the orlistat-treated patients were also low and similar in the intervention and control groups. Gastrointestinal effects were common. The number needed to harm (NNH) for fatty or oily stools was 2,⁴ and the NNH for fecal incontinence was 12.⁵

WHAT'S NEW: Clinicians treating obese kids have cause for optimism

Although the trials included in this review were heterogeneous and many were small, this systematic review provides evidence that intensive, comprehensive behavioral weight loss interventions for obese children can be effective up to 12 months after the conclusion of the program. Family physicians should consider referring obese children and adolescents to such programs—or finding ways to provide supportive strategies themselves.

Sibutramine and orlistat may be helpful in the context of comprehensive, intensive behavioral interventions, although there is no follow-up data to demonstrate long-term safety and weight maintenance after the medication is stopped.

CAVEATS: Little is known about long-term safety of the drugs

There have been few randomized trials of pharmacologic interventions in adolescents and none evaluating weight maintenance after 12 months (or discontinuation of treatment), or assessing long-term safety of the medication.

Sibutramine is not approved by the US Food and Drug Administration (FDA) for use in children or adolescents.⁷ Orlistat is currently approved only for individuals over the age of 12.⁸

In January 2010, an additional contraindication was added to the sibutramine drug label, stating that it is not to be used in patients with a history of cardiovascular disease.⁹ And the FDA is currently investigating a rare association between orlistat and liver injury, although no conclusions have been released.¹⁰ Children and adolescents are particularly vulnerable to long-term side effects, given their relatively young age at the time of drug initiation, so we urge caution with the use of these drugs in this patient population.

CHALLENGES TO IMPLEMENTATION: Intensive approach may be hard to reproduce

Implementation of high-intensity comprehensive interventions for obese children faces a number of roadblocks, including limited availability of programs, cost, and reimbursement. Most of the intensive interventions in these trials took place in specialty centers rather than in primary care offices. Replicating them could require a referral—or significant resources within the primary care setting itself. Yet many, if not most, insurance policies still do not cover such extensive lifestyle interventions. (For information on weight loss interventions for adults, see “Weight loss strategies that really work”).

None of these trials reported on cost or cost effectiveness. Despite the considerable cost of a comprehensive obesity management program, however, a successful weight-maintenance model could be a worthwhile investment in long-term health.

Lastly, the results of this trial should not negate the importance of obesity prevention efforts by parents, who are in the best position to reverse the childhood obesity epidemic.¹¹

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999; awarded by the National Center for Research Resources; the grant is 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 mother brings her 6-year-old son to the emergency department (ED) for treatment of forearm pain after a bicycle accident. clinical examination reveals a swollen and tender wrist. A radiograph confirms a diagnosis of a nondisplaced distal radial fracture. After proper stabilization, the little boy is discharged home, with a visit to his primary care physician scheduled for the following week. if he were your patient, what would you prescribe for outpatient analgesia?

Musculoskeletal trauma is a common pediatric presentation, in both emergency and office settings. In fact, it is estimated that by age 15, one-half to two-thirds of children will have fractured a bone.⁴ Physicians commonly prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids—especially acetaminophen with codeine—as analgesia for children with fractures,⁵ but few studies have directly compared these medications in pediatric patients.

No consensus on analgesia for musculoskeletal pain in kids
Pain associated with an acute fracture is substantial, and most children who incur fractures are managed at home, and thus require effective and well-tolerated oral analgesia. However, prescribing practices vary widely, and there is no consensus regarding the first-line medication for kids with fracture.

A Cochrane review of adult postoperative pain concluded that NSAIDs are effective, and they are commonly prescribed to adult patients for various types of pain.⁶ Fewer studies of pain control in children exist. Before the 2009 study reported on here, there were just 2 RCTs that addressed pediatric musculoskeletal pain in patients presenting to the ED.

In single-dose studies, ibuprofen comes out ahead
The smaller of the 2 trials (N=66) compared ibuprofen alone vs ibuprofen plus oxycodone for suspected orthopedic injury. The researchers found that pain relief was equivalent, but the oxycodone group had more adverse effects.² The larger trial (N=336) compared ibuprofen, acetaminophen, and codeine for acute pediatric musculoskeletal injuries. An hour after receiving their study drug, children in the ibuprofen group had significantly greater reduction in pain than those in either the acetaminophen group or the codeine group. They were also more likely to report adequate analgesia.³ Neither study followed patients after discharge from the ED.

STUDY SUMMARY: New RCT evaluates pain relief once patients go home

The Drendel study was a randomized, controlled, double-blind trial of outpatient analgesia for pediatric fractures.¹ The investigators randomized 336 children ages 4 to 18 years with radiographically confirmed arm fractures to a suspension of either ibuprofen (10 mg/kg) or acetaminophen with codeine (1 mg/kg codeine component per dose), which are recommended dosages. They enrolled a convenience sample of children with nondisplaced fractures that did not require reduction in the ED.

Children were excluded if they weighed more than 60 kg, preferred tablets to liquid medication, sought care more than 12 hours after injury, or had developmental delays or contraindications to any study medication. Also excluded were children—or their parents—who did not speak English and those who were inaccessible by telephone for follow-up.

Study groups had similar baseline demographic and fracture characteristics, and similar pain scores. Patients and their parents were blinded to the assigned drug; all received the same discharge instructions and 2 doses of a rescue medication (the alternate study drug). The primary outcome was use of rescue medication due to failure of the assigned study drug. Secondary outcomes included decrease in pain score, functional outcomes (play, school, eating, sleeping), and satisfaction with the medication.

During the 72 hours after discharge from the ED, patients and parents filled out a standard diary recording pain and medication use. The diaries were returned by mail. Follow-up was good, with about 75% of diaries returned.

Ibuprofen users had fewer problems
Analysis of 244 diaries revealed that less rescue medication was used in the ibuprofen group, although the difference was not statistically significant (20.3% vs 31% [absolute risk reduction, 10.7%], 95% confidence interval, -0.2% to 21.6%). Decrease in mean pain score was the same in both groups. Functional status the day after the injury was better in the ibuprofen group compared with the acetaminophen/codeine group. In addition, 50.9% of patients in the acetaminophen/codeine group reported adverse events, vs 29.5% of those in the ibuprofen group (number needed to harm=4.7).

At the study’s end, children were more satisfied with ibuprofen. Only 10% of patients who took ibuprofen said they would not use it for future fractures; in comparison, 27.5% of patients in the acetaminophen/codeine group said they would not choose to use codeine again.

The authors followed participants for 1 to 4 years through orthopedic clinic records and telephone calls for any long-term adverse orthopedic outcomes. Four cases of refracture at the same site occurred (1.6%), 3 of which were in the acetaminophen/codeine group. There were no cases of nonunion.

WHAT'S NEW: Ibuprofen emerges as first-line agent for kids

Both ibuprofen and acetaminophen with codeine are commonly prescribed for outpatient pediatric analgesia, but this is the first study to compare them head-to-head for outpatient management of postfracture pain. Ibuprofen worked at least as well as acetaminophen with codeine for fracture pain control, and had fewer adverse effects. Children given ibuprofen were better able to eat and play than those given acetaminophen with codeine—an important patient-oriented functional outcome. Patients and their parents were also more satisfied when ED physicians prescribed ibuprofen. This study is consistent with short-term (single-dose) studies and confirms that ibuprofen should be the first-line agent for outpatient analgesia in this group.

CAVEATS: Study did not address NSAIDs’ effect on bone healing

In theory, ibuprofen—like other NSAIDs—can diminish the proinflammatory milieu required for bone turnover and fracture healing. Chart reviews of up to 4 years after the incident fracture found no evidence that ibuprofen delayed healing or increased rates of refracture. However, this study was neither designed nor powered to examine this outcome. Previous studies have found no conclusive evidence that short-term use of NSAIDs impairs fracture healing.^7,8

Results apply only to simple fractures. Patients in this study did not require manipulation or reduction of their fracture, limiting the scope of the authors’ recommendation to simple arm fractures. More severe injury may require narcotic analgesia. One can assume, based on this and other supporting literature, that the findings extrapolate to other similarly painful pediatric musculoskeletal injuries.²

Twenty-five percent of subjects were lost to follow-up. Follow-up diaries were available from about 75% of the participants. It is possible that a clearer beneficial outcome would have been found with 1 of the analgesics studied if the response rate had been higher. Because this study is consistent with the previous ED-only studies comparing ibuprofen with acetaminophen plus codeine, however, it is unlikely that a higher response rate would find ibuprofen inferior to acetaminophen plus codeine.

CHALLENGES TO IMPLEMENTATION: Parents—or patients—may expect an Rx

Prescribing an effective, common, inexpensive, and well-tolerated oral medication should have no barriers to implementation. Still, use of an over-the-counter medication, however effective, may face resistance from patients or parents who expect “something more” for fracture pain.

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is 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 mother brings her 6-year-old son to the emergency department (ED) for treatment of forearm pain after a bicycle accident. clinical examination reveals a swollen and tender wrist. A radiograph confirms a diagnosis of a nondisplaced distal radial fracture. After proper stabilization, the little boy is discharged home, with a visit to his primary care physician scheduled for the following week. if he were your patient, what would you prescribe for outpatient analgesia?

Musculoskeletal trauma is a common pediatric presentation, in both emergency and office settings. In fact, it is estimated that by age 15, one-half to two-thirds of children will have fractured a bone.⁴ Physicians commonly prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids—especially acetaminophen with codeine—as analgesia for children with fractures,⁵ but few studies have directly compared these medications in pediatric patients.

No consensus on analgesia for musculoskeletal pain in kids
Pain associated with an acute fracture is substantial, and most children who incur fractures are managed at home, and thus require effective and well-tolerated oral analgesia. However, prescribing practices vary widely, and there is no consensus regarding the first-line medication for kids with fracture.

A Cochrane review of adult postoperative pain concluded that NSAIDs are effective, and they are commonly prescribed to adult patients for various types of pain.⁶ Fewer studies of pain control in children exist. Before the 2009 study reported on here, there were just 2 RCTs that addressed pediatric musculoskeletal pain in patients presenting to the ED.

In single-dose studies, ibuprofen comes out ahead
The smaller of the 2 trials (N=66) compared ibuprofen alone vs ibuprofen plus oxycodone for suspected orthopedic injury. The researchers found that pain relief was equivalent, but the oxycodone group had more adverse effects.² The larger trial (N=336) compared ibuprofen, acetaminophen, and codeine for acute pediatric musculoskeletal injuries. An hour after receiving their study drug, children in the ibuprofen group had significantly greater reduction in pain than those in either the acetaminophen group or the codeine group. They were also more likely to report adequate analgesia.³ Neither study followed patients after discharge from the ED.

STUDY SUMMARY: New RCT evaluates pain relief once patients go home

The Drendel study was a randomized, controlled, double-blind trial of outpatient analgesia for pediatric fractures.¹ The investigators randomized 336 children ages 4 to 18 years with radiographically confirmed arm fractures to a suspension of either ibuprofen (10 mg/kg) or acetaminophen with codeine (1 mg/kg codeine component per dose), which are recommended dosages. They enrolled a convenience sample of children with nondisplaced fractures that did not require reduction in the ED.

Children were excluded if they weighed more than 60 kg, preferred tablets to liquid medication, sought care more than 12 hours after injury, or had developmental delays or contraindications to any study medication. Also excluded were children—or their parents—who did not speak English and those who were inaccessible by telephone for follow-up.

Study groups had similar baseline demographic and fracture characteristics, and similar pain scores. Patients and their parents were blinded to the assigned drug; all received the same discharge instructions and 2 doses of a rescue medication (the alternate study drug). The primary outcome was use of rescue medication due to failure of the assigned study drug. Secondary outcomes included decrease in pain score, functional outcomes (play, school, eating, sleeping), and satisfaction with the medication.

During the 72 hours after discharge from the ED, patients and parents filled out a standard diary recording pain and medication use. The diaries were returned by mail. Follow-up was good, with about 75% of diaries returned.

Ibuprofen users had fewer problems
Analysis of 244 diaries revealed that less rescue medication was used in the ibuprofen group, although the difference was not statistically significant (20.3% vs 31% [absolute risk reduction, 10.7%], 95% confidence interval, -0.2% to 21.6%). Decrease in mean pain score was the same in both groups. Functional status the day after the injury was better in the ibuprofen group compared with the acetaminophen/codeine group. In addition, 50.9% of patients in the acetaminophen/codeine group reported adverse events, vs 29.5% of those in the ibuprofen group (number needed to harm=4.7).

At the study’s end, children were more satisfied with ibuprofen. Only 10% of patients who took ibuprofen said they would not use it for future fractures; in comparison, 27.5% of patients in the acetaminophen/codeine group said they would not choose to use codeine again.

The authors followed participants for 1 to 4 years through orthopedic clinic records and telephone calls for any long-term adverse orthopedic outcomes. Four cases of refracture at the same site occurred (1.6%), 3 of which were in the acetaminophen/codeine group. There were no cases of nonunion.

WHAT'S NEW: Ibuprofen emerges as first-line agent for kids

Both ibuprofen and acetaminophen with codeine are commonly prescribed for outpatient pediatric analgesia, but this is the first study to compare them head-to-head for outpatient management of postfracture pain. Ibuprofen worked at least as well as acetaminophen with codeine for fracture pain control, and had fewer adverse effects. Children given ibuprofen were better able to eat and play than those given acetaminophen with codeine—an important patient-oriented functional outcome. Patients and their parents were also more satisfied when ED physicians prescribed ibuprofen. This study is consistent with short-term (single-dose) studies and confirms that ibuprofen should be the first-line agent for outpatient analgesia in this group.

CAVEATS: Study did not address NSAIDs’ effect on bone healing

In theory, ibuprofen—like other NSAIDs—can diminish the proinflammatory milieu required for bone turnover and fracture healing. Chart reviews of up to 4 years after the incident fracture found no evidence that ibuprofen delayed healing or increased rates of refracture. However, this study was neither designed nor powered to examine this outcome. Previous studies have found no conclusive evidence that short-term use of NSAIDs impairs fracture healing.^7,8

Results apply only to simple fractures. Patients in this study did not require manipulation or reduction of their fracture, limiting the scope of the authors’ recommendation to simple arm fractures. More severe injury may require narcotic analgesia. One can assume, based on this and other supporting literature, that the findings extrapolate to other similarly painful pediatric musculoskeletal injuries.²

Twenty-five percent of subjects were lost to follow-up. Follow-up diaries were available from about 75% of the participants. It is possible that a clearer beneficial outcome would have been found with 1 of the analgesics studied if the response rate had been higher. Because this study is consistent with the previous ED-only studies comparing ibuprofen with acetaminophen plus codeine, however, it is unlikely that a higher response rate would find ibuprofen inferior to acetaminophen plus codeine.

CHALLENGES TO IMPLEMENTATION: Parents—or patients—may expect an Rx

Prescribing an effective, common, inexpensive, and well-tolerated oral medication should have no barriers to implementation. Still, use of an over-the-counter medication, however effective, may face resistance from patients or parents who expect “something more” for fracture pain.

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is 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 mother brings her 6-year-old son to the emergency department (ED) for treatment of forearm pain after a bicycle accident. clinical examination reveals a swollen and tender wrist. A radiograph confirms a diagnosis of a nondisplaced distal radial fracture. After proper stabilization, the little boy is discharged home, with a visit to his primary care physician scheduled for the following week. if he were your patient, what would you prescribe for outpatient analgesia?

Musculoskeletal trauma is a common pediatric presentation, in both emergency and office settings. In fact, it is estimated that by age 15, one-half to two-thirds of children will have fractured a bone.⁴ Physicians commonly prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids—especially acetaminophen with codeine—as analgesia for children with fractures,⁵ but few studies have directly compared these medications in pediatric patients.

No consensus on analgesia for musculoskeletal pain in kids
Pain associated with an acute fracture is substantial, and most children who incur fractures are managed at home, and thus require effective and well-tolerated oral analgesia. However, prescribing practices vary widely, and there is no consensus regarding the first-line medication for kids with fracture.

A Cochrane review of adult postoperative pain concluded that NSAIDs are effective, and they are commonly prescribed to adult patients for various types of pain.⁶ Fewer studies of pain control in children exist. Before the 2009 study reported on here, there were just 2 RCTs that addressed pediatric musculoskeletal pain in patients presenting to the ED.

In single-dose studies, ibuprofen comes out ahead
The smaller of the 2 trials (N=66) compared ibuprofen alone vs ibuprofen plus oxycodone for suspected orthopedic injury. The researchers found that pain relief was equivalent, but the oxycodone group had more adverse effects.² The larger trial (N=336) compared ibuprofen, acetaminophen, and codeine for acute pediatric musculoskeletal injuries. An hour after receiving their study drug, children in the ibuprofen group had significantly greater reduction in pain than those in either the acetaminophen group or the codeine group. They were also more likely to report adequate analgesia.³ Neither study followed patients after discharge from the ED.

STUDY SUMMARY: New RCT evaluates pain relief once patients go home

The Drendel study was a randomized, controlled, double-blind trial of outpatient analgesia for pediatric fractures.¹ The investigators randomized 336 children ages 4 to 18 years with radiographically confirmed arm fractures to a suspension of either ibuprofen (10 mg/kg) or acetaminophen with codeine (1 mg/kg codeine component per dose), which are recommended dosages. They enrolled a convenience sample of children with nondisplaced fractures that did not require reduction in the ED.

Children were excluded if they weighed more than 60 kg, preferred tablets to liquid medication, sought care more than 12 hours after injury, or had developmental delays or contraindications to any study medication. Also excluded were children—or their parents—who did not speak English and those who were inaccessible by telephone for follow-up.

Study groups had similar baseline demographic and fracture characteristics, and similar pain scores. Patients and their parents were blinded to the assigned drug; all received the same discharge instructions and 2 doses of a rescue medication (the alternate study drug). The primary outcome was use of rescue medication due to failure of the assigned study drug. Secondary outcomes included decrease in pain score, functional outcomes (play, school, eating, sleeping), and satisfaction with the medication.

During the 72 hours after discharge from the ED, patients and parents filled out a standard diary recording pain and medication use. The diaries were returned by mail. Follow-up was good, with about 75% of diaries returned.

Ibuprofen users had fewer problems
Analysis of 244 diaries revealed that less rescue medication was used in the ibuprofen group, although the difference was not statistically significant (20.3% vs 31% [absolute risk reduction, 10.7%], 95% confidence interval, -0.2% to 21.6%). Decrease in mean pain score was the same in both groups. Functional status the day after the injury was better in the ibuprofen group compared with the acetaminophen/codeine group. In addition, 50.9% of patients in the acetaminophen/codeine group reported adverse events, vs 29.5% of those in the ibuprofen group (number needed to harm=4.7).

At the study’s end, children were more satisfied with ibuprofen. Only 10% of patients who took ibuprofen said they would not use it for future fractures; in comparison, 27.5% of patients in the acetaminophen/codeine group said they would not choose to use codeine again.

The authors followed participants for 1 to 4 years through orthopedic clinic records and telephone calls for any long-term adverse orthopedic outcomes. Four cases of refracture at the same site occurred (1.6%), 3 of which were in the acetaminophen/codeine group. There were no cases of nonunion.

WHAT'S NEW: Ibuprofen emerges as first-line agent for kids

Both ibuprofen and acetaminophen with codeine are commonly prescribed for outpatient pediatric analgesia, but this is the first study to compare them head-to-head for outpatient management of postfracture pain. Ibuprofen worked at least as well as acetaminophen with codeine for fracture pain control, and had fewer adverse effects. Children given ibuprofen were better able to eat and play than those given acetaminophen with codeine—an important patient-oriented functional outcome. Patients and their parents were also more satisfied when ED physicians prescribed ibuprofen. This study is consistent with short-term (single-dose) studies and confirms that ibuprofen should be the first-line agent for outpatient analgesia in this group.

CAVEATS: Study did not address NSAIDs’ effect on bone healing

In theory, ibuprofen—like other NSAIDs—can diminish the proinflammatory milieu required for bone turnover and fracture healing. Chart reviews of up to 4 years after the incident fracture found no evidence that ibuprofen delayed healing or increased rates of refracture. However, this study was neither designed nor powered to examine this outcome. Previous studies have found no conclusive evidence that short-term use of NSAIDs impairs fracture healing.^7,8

Results apply only to simple fractures. Patients in this study did not require manipulation or reduction of their fracture, limiting the scope of the authors’ recommendation to simple arm fractures. More severe injury may require narcotic analgesia. One can assume, based on this and other supporting literature, that the findings extrapolate to other similarly painful pediatric musculoskeletal injuries.²

Twenty-five percent of subjects were lost to follow-up. Follow-up diaries were available from about 75% of the participants. It is possible that a clearer beneficial outcome would have been found with 1 of the analgesics studied if the response rate had been higher. Because this study is consistent with the previous ED-only studies comparing ibuprofen with acetaminophen plus codeine, however, it is unlikely that a higher response rate would find ibuprofen inferior to acetaminophen plus codeine.

CHALLENGES TO IMPLEMENTATION: Parents—or patients—may expect an Rx

Prescribing an effective, common, inexpensive, and well-tolerated oral medication should have no barriers to implementation. Still, use of an over-the-counter medication, however effective, may face resistance from patients or parents who expect “something more” for fracture pain.

Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources; the grant is 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 man comes to see you 1 day after injuring his left ankle, which he inverted while playing racquetball in a semicompetitive league. After a clinical exam, you diagnose an ankle sprain. You advise him to wrap the ankle for protection and recommend rest, ice, compression, and elevation. Besides treatment for the current sprain, however, he asks what he can do after recovery to prevent ankle reinjury.

What can you tell him?

An estimated 23,000 ankle sprains occur every day in the United States, which amounts to approximately 1 in every 10,000 people.² In many sports, ankle sprain is the most common injury,³ partly because an athlete who incurs a first ankle sprain is at increased risk of another.^4-6 The risk of reinjury is highest in the year immediately following the initial sprain.^6-8

Long-term effects of repeat sprains
About half of recurrent ankle sprains result in chronic pain or disability, so preventing repeat sprains is an important patient-oriented treatment goal. Various modalities, including bracing, taping, and warm-up and strengthening exercises, have been used to prevent recurrence of ankle sprain. Proprioceptive training has also been suggested.^5,9 A Cochrane review in 2001 found limited evidence for reduction of ankle sprain recurrence after proprioceptive exercises.¹⁰ Until the study reviewed in this PURL, its effectiveness remained uncertain.

STUDY SUMMARY: Exercise program reduces risk

Hupperets et al¹ investigated the effectiveness of a home-based proprioceptive training program to prevent ankle sprain recurrence. Enrollees (N=522) in this well-done RCT were active sports participants ranging in age from 12 to 70 years, all of whom had incurred ankle sprains in the preceding 2 months. They were recruited throughout The Netherlands using a variety of medical channels—emergency departments, general practices, and physical therapy offices—and advertisements in newspapers and sports magazines, at sports tournaments, and on the Internet.

The athletes were randomized to the intervention or control group, with stratification for sex, type of enrollment, and type of care they initially received for the ankle sprain—which the participants in both groups received without interference from the authors. (Among the enrollees were 181 people who did not receive any medical care for their sprains.)

Participants in the intervention group were given an instructional DVD, a balance board, and an exercise sheet, with further instructions available on a Web site. They were told to engage in 3 self-guided treatment sessions per week for 8 weeks, with a maximum duration of 30 minutes per session. The regimen included a series of exercises such as the 1-legged stance, in which the patient slightly flexes the weight-bearing leg at the knee, hip, and ankle while the foot of the other leg is off the floor, then switches legs after a minute. The exercises involved increasing levels of difficulty—performed on an even surface, on an even surface with the eyes closed, or on a balance board.

The primary outcome was a self-reported new sprain of the previously injured ankle during 1000 hours of exposure to sports in a year of follow-up. Severe sprain—defined as a sprain leading to loss of sports time or resulting in health care costs or lost productivity—was a secondary outcome. Cox regression analysis was used to compare risk of a recurrent ankle sprain between the intervention and control groups, using an intention-to-treat analysis.

At the 1-year point, 56 of the 256 participants in the intervention group (22%) and 89 of the 266 participants in the control group (33%) reported recurrent ankle sprains. The risk of recurrence per 1000 hours of exposure for the intervention group was significantly lower (relative risk [RR]=0.63; 95% confidence interval [CI], 0.45–0.88) compared with the control group. Nine people would need to be treated to prevent 1 recurrent ankle sprain.

Similarly, significantly lower risks for severe sprains were found for the intervention group, as indicated by loss of sports time (RR=0.53; 95% CI, 0.32–0.88) and health care costs (RR=0.25; 95% CI, 0.12–0.50).

WHAT’S NEW?: High-quality study supports self-guided training program

This is the first RCT to assess the effect of a nonsupervised home-based proprioceptive training program, in addition to usual care, on the recurrence of ankle sprain. Two earlier studies had evaluated balance board exercises to prevent initial ankle injuries in young athletes, and both found these exercises to be effective.^8,11 But prior studies evaluating prevention of recurrent ankle sprain have had methodology weaknesses or small sample sizes.^12-14

One other RCT had studied the effect of an exercise program that included balance boards on the risk of ankle sprain recurrence and found a significant difference in favor or the intervention group (absolute risk reduction=22%).¹⁵ But the exercise program in that study was supervised by professionals rather than self-guided by patients. The study was also marred by significant loss to follow-up (27%), and the information on reinjury was collected retrospectively a year after the acute ankle sprain.

By comparison, the study done by Hupperets et al had a large sample size, minimal loss to follow-up (14%), and monthly check-in with patients to assess reinjury. The results show an absolute reduction of 11% in the risk of recurrence of ankle sprain. The evidence brought forth by this high-quality RCT supports adding a home-based proprioceptive training program for every patient with an acute ankle sprain to reduce the incidence of sprain recurrence.

CAVEATS: Will patients do their exercises?

One concern highlighted by this study is compliance with the treatment regimen. Only 23% of those in the intervention group fully complied with the 8-week program, 29% were partially compliant, 35% were not compliant, and 13% were of unknown compliance.

We think these findings reflect the compliance seen in the real world, so it is encouraging to know that the intervention was nonetheless effective. Clearly, some proprioceptive training is better than none; the optimal amount is not known.

Generalizability is another concern, since this study focused on athletes. However, the investigators included a wide spectrum of patients (ages 12-70 years, male and female, and those engaged in all levels of sports activity). Furthermore, since the mechanism of injury for lateral ankle sprain is generally the same, we think it is reasonable to assume that ankle sprains not related to sports would benefit from a proprioceptive program, as well.

CHALLENGES TO IMPLEMENTATION: No significant barriers exist

The treatment does not have any significant adverse effects and should be easy to recommend. Balance boards can be obtained from a sporting goods supplier or online, at a cost of $13 to $35. Some busy physician practices may not have the time or staff to teach patients how to carry out these exercises. In that case, a 1-time referral to a physical therapist should be sufficient.

Acknowledgment
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 man comes to see you 1 day after injuring his left ankle, which he inverted while playing racquetball in a semicompetitive league. After a clinical exam, you diagnose an ankle sprain. You advise him to wrap the ankle for protection and recommend rest, ice, compression, and elevation. Besides treatment for the current sprain, however, he asks what he can do after recovery to prevent ankle reinjury.

What can you tell him?

An estimated 23,000 ankle sprains occur every day in the United States, which amounts to approximately 1 in every 10,000 people.² In many sports, ankle sprain is the most common injury,³ partly because an athlete who incurs a first ankle sprain is at increased risk of another.^4-6 The risk of reinjury is highest in the year immediately following the initial sprain.^6-8

Long-term effects of repeat sprains
About half of recurrent ankle sprains result in chronic pain or disability, so preventing repeat sprains is an important patient-oriented treatment goal. Various modalities, including bracing, taping, and warm-up and strengthening exercises, have been used to prevent recurrence of ankle sprain. Proprioceptive training has also been suggested.^5,9 A Cochrane review in 2001 found limited evidence for reduction of ankle sprain recurrence after proprioceptive exercises.¹⁰ Until the study reviewed in this PURL, its effectiveness remained uncertain.

STUDY SUMMARY: Exercise program reduces risk

Hupperets et al¹ investigated the effectiveness of a home-based proprioceptive training program to prevent ankle sprain recurrence. Enrollees (N=522) in this well-done RCT were active sports participants ranging in age from 12 to 70 years, all of whom had incurred ankle sprains in the preceding 2 months. They were recruited throughout The Netherlands using a variety of medical channels—emergency departments, general practices, and physical therapy offices—and advertisements in newspapers and sports magazines, at sports tournaments, and on the Internet.

The athletes were randomized to the intervention or control group, with stratification for sex, type of enrollment, and type of care they initially received for the ankle sprain—which the participants in both groups received without interference from the authors. (Among the enrollees were 181 people who did not receive any medical care for their sprains.)

Participants in the intervention group were given an instructional DVD, a balance board, and an exercise sheet, with further instructions available on a Web site. They were told to engage in 3 self-guided treatment sessions per week for 8 weeks, with a maximum duration of 30 minutes per session. The regimen included a series of exercises such as the 1-legged stance, in which the patient slightly flexes the weight-bearing leg at the knee, hip, and ankle while the foot of the other leg is off the floor, then switches legs after a minute. The exercises involved increasing levels of difficulty—performed on an even surface, on an even surface with the eyes closed, or on a balance board.

The primary outcome was a self-reported new sprain of the previously injured ankle during 1000 hours of exposure to sports in a year of follow-up. Severe sprain—defined as a sprain leading to loss of sports time or resulting in health care costs or lost productivity—was a secondary outcome. Cox regression analysis was used to compare risk of a recurrent ankle sprain between the intervention and control groups, using an intention-to-treat analysis.

At the 1-year point, 56 of the 256 participants in the intervention group (22%) and 89 of the 266 participants in the control group (33%) reported recurrent ankle sprains. The risk of recurrence per 1000 hours of exposure for the intervention group was significantly lower (relative risk [RR]=0.63; 95% confidence interval [CI], 0.45–0.88) compared with the control group. Nine people would need to be treated to prevent 1 recurrent ankle sprain.

Similarly, significantly lower risks for severe sprains were found for the intervention group, as indicated by loss of sports time (RR=0.53; 95% CI, 0.32–0.88) and health care costs (RR=0.25; 95% CI, 0.12–0.50).

WHAT’S NEW?: High-quality study supports self-guided training program

This is the first RCT to assess the effect of a nonsupervised home-based proprioceptive training program, in addition to usual care, on the recurrence of ankle sprain. Two earlier studies had evaluated balance board exercises to prevent initial ankle injuries in young athletes, and both found these exercises to be effective.^8,11 But prior studies evaluating prevention of recurrent ankle sprain have had methodology weaknesses or small sample sizes.^12-14

One other RCT had studied the effect of an exercise program that included balance boards on the risk of ankle sprain recurrence and found a significant difference in favor or the intervention group (absolute risk reduction=22%).¹⁵ But the exercise program in that study was supervised by professionals rather than self-guided by patients. The study was also marred by significant loss to follow-up (27%), and the information on reinjury was collected retrospectively a year after the acute ankle sprain.

By comparison, the study done by Hupperets et al had a large sample size, minimal loss to follow-up (14%), and monthly check-in with patients to assess reinjury. The results show an absolute reduction of 11% in the risk of recurrence of ankle sprain. The evidence brought forth by this high-quality RCT supports adding a home-based proprioceptive training program for every patient with an acute ankle sprain to reduce the incidence of sprain recurrence.

CAVEATS: Will patients do their exercises?

One concern highlighted by this study is compliance with the treatment regimen. Only 23% of those in the intervention group fully complied with the 8-week program, 29% were partially compliant, 35% were not compliant, and 13% were of unknown compliance.

We think these findings reflect the compliance seen in the real world, so it is encouraging to know that the intervention was nonetheless effective. Clearly, some proprioceptive training is better than none; the optimal amount is not known.

Generalizability is another concern, since this study focused on athletes. However, the investigators included a wide spectrum of patients (ages 12-70 years, male and female, and those engaged in all levels of sports activity). Furthermore, since the mechanism of injury for lateral ankle sprain is generally the same, we think it is reasonable to assume that ankle sprains not related to sports would benefit from a proprioceptive program, as well.

CHALLENGES TO IMPLEMENTATION: No significant barriers exist

The treatment does not have any significant adverse effects and should be easy to recommend. Balance boards can be obtained from a sporting goods supplier or online, at a cost of $13 to $35. Some busy physician practices may not have the time or staff to teach patients how to carry out these exercises. In that case, a 1-time referral to a physical therapist should be sufficient.

Acknowledgment
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 man comes to see you 1 day after injuring his left ankle, which he inverted while playing racquetball in a semicompetitive league. After a clinical exam, you diagnose an ankle sprain. You advise him to wrap the ankle for protection and recommend rest, ice, compression, and elevation. Besides treatment for the current sprain, however, he asks what he can do after recovery to prevent ankle reinjury.

What can you tell him?

An estimated 23,000 ankle sprains occur every day in the United States, which amounts to approximately 1 in every 10,000 people.² In many sports, ankle sprain is the most common injury,³ partly because an athlete who incurs a first ankle sprain is at increased risk of another.^4-6 The risk of reinjury is highest in the year immediately following the initial sprain.^6-8

Long-term effects of repeat sprains
About half of recurrent ankle sprains result in chronic pain or disability, so preventing repeat sprains is an important patient-oriented treatment goal. Various modalities, including bracing, taping, and warm-up and strengthening exercises, have been used to prevent recurrence of ankle sprain. Proprioceptive training has also been suggested.^5,9 A Cochrane review in 2001 found limited evidence for reduction of ankle sprain recurrence after proprioceptive exercises.¹⁰ Until the study reviewed in this PURL, its effectiveness remained uncertain.

STUDY SUMMARY: Exercise program reduces risk

Hupperets et al¹ investigated the effectiveness of a home-based proprioceptive training program to prevent ankle sprain recurrence. Enrollees (N=522) in this well-done RCT were active sports participants ranging in age from 12 to 70 years, all of whom had incurred ankle sprains in the preceding 2 months. They were recruited throughout The Netherlands using a variety of medical channels—emergency departments, general practices, and physical therapy offices—and advertisements in newspapers and sports magazines, at sports tournaments, and on the Internet.

The athletes were randomized to the intervention or control group, with stratification for sex, type of enrollment, and type of care they initially received for the ankle sprain—which the participants in both groups received without interference from the authors. (Among the enrollees were 181 people who did not receive any medical care for their sprains.)

Participants in the intervention group were given an instructional DVD, a balance board, and an exercise sheet, with further instructions available on a Web site. They were told to engage in 3 self-guided treatment sessions per week for 8 weeks, with a maximum duration of 30 minutes per session. The regimen included a series of exercises such as the 1-legged stance, in which the patient slightly flexes the weight-bearing leg at the knee, hip, and ankle while the foot of the other leg is off the floor, then switches legs after a minute. The exercises involved increasing levels of difficulty—performed on an even surface, on an even surface with the eyes closed, or on a balance board.

The primary outcome was a self-reported new sprain of the previously injured ankle during 1000 hours of exposure to sports in a year of follow-up. Severe sprain—defined as a sprain leading to loss of sports time or resulting in health care costs or lost productivity—was a secondary outcome. Cox regression analysis was used to compare risk of a recurrent ankle sprain between the intervention and control groups, using an intention-to-treat analysis.

At the 1-year point, 56 of the 256 participants in the intervention group (22%) and 89 of the 266 participants in the control group (33%) reported recurrent ankle sprains. The risk of recurrence per 1000 hours of exposure for the intervention group was significantly lower (relative risk [RR]=0.63; 95% confidence interval [CI], 0.45–0.88) compared with the control group. Nine people would need to be treated to prevent 1 recurrent ankle sprain.

Similarly, significantly lower risks for severe sprains were found for the intervention group, as indicated by loss of sports time (RR=0.53; 95% CI, 0.32–0.88) and health care costs (RR=0.25; 95% CI, 0.12–0.50).

WHAT’S NEW?: High-quality study supports self-guided training program

This is the first RCT to assess the effect of a nonsupervised home-based proprioceptive training program, in addition to usual care, on the recurrence of ankle sprain. Two earlier studies had evaluated balance board exercises to prevent initial ankle injuries in young athletes, and both found these exercises to be effective.^8,11 But prior studies evaluating prevention of recurrent ankle sprain have had methodology weaknesses or small sample sizes.^12-14

One other RCT had studied the effect of an exercise program that included balance boards on the risk of ankle sprain recurrence and found a significant difference in favor or the intervention group (absolute risk reduction=22%).¹⁵ But the exercise program in that study was supervised by professionals rather than self-guided by patients. The study was also marred by significant loss to follow-up (27%), and the information on reinjury was collected retrospectively a year after the acute ankle sprain.

By comparison, the study done by Hupperets et al had a large sample size, minimal loss to follow-up (14%), and monthly check-in with patients to assess reinjury. The results show an absolute reduction of 11% in the risk of recurrence of ankle sprain. The evidence brought forth by this high-quality RCT supports adding a home-based proprioceptive training program for every patient with an acute ankle sprain to reduce the incidence of sprain recurrence.

CAVEATS: Will patients do their exercises?

One concern highlighted by this study is compliance with the treatment regimen. Only 23% of those in the intervention group fully complied with the 8-week program, 29% were partially compliant, 35% were not compliant, and 13% were of unknown compliance.

We think these findings reflect the compliance seen in the real world, so it is encouraging to know that the intervention was nonetheless effective. Clearly, some proprioceptive training is better than none; the optimal amount is not known.

Generalizability is another concern, since this study focused on athletes. However, the investigators included a wide spectrum of patients (ages 12-70 years, male and female, and those engaged in all levels of sports activity). Furthermore, since the mechanism of injury for lateral ankle sprain is generally the same, we think it is reasonable to assume that ankle sprains not related to sports would benefit from a proprioceptive program, as well.

CHALLENGES TO IMPLEMENTATION: No significant barriers exist

The treatment does not have any significant adverse effects and should be easy to recommend. Balance boards can be obtained from a sporting goods supplier or online, at a cost of $13 to $35. Some busy physician practices may not have the time or staff to teach patients how to carry out these exercises. In that case, a 1-time referral to a physical therapist should be sufficient.

Acknowledgment
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 34-year-old woman comes to your office and asks to be taken off the paroxetine you prescribed for her 4 months ago. The medication is working well; her depression has been in remission for at least 12 weeks. But she no longer enjoys sex. She used to have a healthy libido and satisfying arousal and orgasm, but since starting the antidepressant, her sexual interest and pleasure have been low.

Although she’s afraid of sinking back into a depression without the medication, she’s willing to take the risk. If she were your patient, what alternatives would you suggest?

Sexual dysfunction affects an estimated 30% to 50% of patients on selective and nonselective SRIs, and some studies report rates as high as 70% to 80%.² Many patients stop taking these antidepressants prematurely, often because of sexual side effects.^3,4

Phosphodiesterase type 5 (PDE-5) inhibitors are well established as an effective treatment for erectile dysfunction,⁵ and randomized controlled trials (RCTs) have shown sildenafil to be effective in treating male SRI-induced sexual impairment.^6,7 For women, there has been no parallel evidence-based treatment.

Limited options, with little support

Typically, women who reported antidepressant-associated sexual disturbances have been offered options for which there was only weak evidence—dose changes or augmentation with another agent, switching to another antidepressant, or taking occasional drug holidays. A 2004 Cochrane review found that there were no RCTs involving dose changes or drug holidays.⁸ Among studies of the efficacy of switching to a different drug, nefazodone was the only agent whose use was supported by a double-blind RCT.⁹ Augmentation trials of a wide range of medications and supplements—including amantadine, bupropion, buspirone, granisetron, mirtazapine, olanzapine, ephedrine, ginkgo biloba, and yohimbine—yielded mixed results. Indeed, the research found that some were no better than placebo.

PDE-5 inhibitors for women? Inconclusive studies to date

Female sexual dysfunction is generally divided into 4 domains: disorders of desire, arousal, orgasm, or pain. Decreased desire and delayed or absent orgasm are the most common sexual side effects of SRI antidepressants in women.¹⁰ Several studies of PDE-5 inhibitors in this patient population have had positive results,^11-15 so there has been good reason to think that they might help this subset of women. However, all the studies were small and nonblinded, and therefore inconclusive—until now.

STUDY SUMMARY: Finally, a well-done RCT provides some answers

Investigators enrolled 98 premenopausal women from 7 US research centers in a double-blind randomized trial. To qualify, participants had to be diagnosed with major depression in remission, be taking a selective or nonselective SRI for >8 weeks, and be on a stable dose for >4 weeks. They also had to meet Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for substance-induced sexual dysfunction lasting >4 weeks, but have no history of sexual impairment independent of antidepressants. Finally, participants had to engage in some form of regular sexual activity—intercourse, oral sex, and masturbation all qualified—at least twice a month, and be willing to continue efforts to have sex at least once a week during the study. Women with other medical, psychiatric, or sexual problems were excluded, as were those who were pregnant, breastfeeding, or able to become pregnant and not using reliable contraception.

Participants were randomized to receive 50 mg of sildenafil (n=49) or a matching placebo tablet (n=49), which they were instructed to take 1 to 2 hours before sexual activity. The dose could be adjusted to 2 tablets (100 mg sildenafil) based on investigator assessment of the patient’s response to the initial dose. Participants and all study personnel were blinded to group assignment.

The primary outcome was change from baseline to end-point in the Clinical Global Impression Scale, a clinician-rated scale based on review of patient symptoms that was adapted to evaluate sexual function. Secondary outcomes were changes in 3 other sexual function scales, the Hamilton Rating Scale for Depression, and measured hormone levels.

Investigators followed the women for 8 weeks, measuring outcomes at 2, 4, and 8 weeks.

Sildenafil is better than placebo

Using an intention-to-treat analysis with the last measurement (2, 4, or 8 weeks) as the end-point, both the treatment and placebo groups experienced improvement in sexual function. The sildenafil group improved more than the placebo group. On the Clinical Global Impression Scale (1 to 7, with higher scores indicating worse sexual function), sildenafil users went from a mean of 4.8 to 2.8, while placebo users went from a mean of 4.7 to 3.6. The difference in mean change from baseline was 0.8 (95% confidence interval [CI] 0.6-1.0; P=.001). Using a more conservative analysis in which participants who did not return for the 8-week follow-up visit were assumed to have returned to baseline, the difference in mean change from baseline was smaller (0.6, 95% CI, 0.3-0.8; P=0.03) but still statistically significant.

Orgasmic function shows significant improvement

The sexual function scales used as secondary outcomes provided more detail about which types of sexual dysfunction benefited from sildenafil. On all 3 scales, orgasmic function significantly favored sildenafil over placebo. In the domains of desire, arousal, and pain disorders, small to moderate improvements were seen in both groups, with no statistically significant differences. One potential confounder—a difference in the course of participants’ underlying depression— was ruled out because depression scale results remained unchanged from baseline to endpoint in both groups.

Baseline levels of cortisone, estradiol, follicle-stimulating hormone, leuteinizing hormone, progesterone, prolactin, sex hormone-binding globulin, testosterone, thyroid-stimulating hormone, and thyroxine, were normal, with no differences between the sildenafil and placebo groups.

WHAT’S NEW: Women have an evidence-based option

Like their male counterparts, we can now offer women whose depression is effectively treated by SRI antidepressants—and who are motivated to stay sexually active despite medication-associated side effects—an effective pharmacotherapeutic treatment.

CAVEATS: Side effects and study funding are worth noting

Side effects. Significantly more participants in the sildenafil group vs the placebo group experienced the following side effects: headache (43% vs 27%), visual disturbance (14% vs 2%), dyspepsia (12% vs 0%), flushing (24% vs 0%), nasal congestion (37% vs 6%), and palpitations (8% vs 2%). Nausea was the only side effect that was more common in the placebo group, reported by only 2% of those in the intervention group but 16% of those on placebo.

No serious adverse events occurred, however, and the medication appears to have been well tolerated overall, despite relatively high rates of side effects. Participants in the intervention group used an average of 5 doses of sildenafil per 2-week interval, the same number as those in the placebo group.

Small treatment effect. The difference in response between sildenafil and placebo was not large: 0.8 points on a 7-point scale. But this difference is likely a clinically meaningful effect to the women with this problem.

Drug company funding. Pfizer, the maker of Viagra, funded this study through an investigator-initiated grant. Some researchers argue that female sexual dysfunction has been defined, or even invented, by drug companies seeking to create new markets for their products.¹⁶ This concern, coupled with the fact that this is the only double-blind randomized trial to show that sildenafil benefits women with antidepressant-associated sexual impairment, raises the question of whether this finding will be replicated in future trials.

We were reassured by the authors’ statement that Pfizer had no role in the study design, implementation, analysis, or manuscript preparation. And we know from clinical practice that women do suffer from SRI-induced sexual side effects, and sometimes stop taking much-needed antidepressants because the medication interferes with their ability to have a satisfying sex life. We believe this study was well done and offers a promising new therapy that deserves consideration. We hope that additional trials will follow and that investigators and journals will not hesitate to publish negative results.

Not for all women with sexual dysfunction

It’s a safe bet that these findings will be used to market sildenafil to women. It is therefore important for physicians and patients to keep in mind that this trial focused on a well-defined subset of women with sexual dysfunction: those on a stable dose of an SRI, with depression in remission, who were otherwise healthy and not pregnant, breastfeeding, or planning pregnancy, and who were motivated to be sexually active. Although this study does support the use of sildenafil for women in this subset, it does not support the use of PDE-5 inhibitors such as sildenafil for all women with sexual difficulties.

CHALLENGES TO IMPLEMENTATION: You have to ask!

Studies have repeatedly found that many women who experience sexual problems do not broach the subject with their doctors.¹⁷ So don’t wait for your female patients to bring it up. Sexual side effects are common enough with SRI antidepressants that all prescribers should mention the possibility in advance. Tell patients to let you know if they develop medication-related sexual dysfunction, and reassure them that there are treatments that can help.

Acknowledgment

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.

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 34-year-old woman comes to your office and asks to be taken off the paroxetine you prescribed for her 4 months ago. The medication is working well; her depression has been in remission for at least 12 weeks. But she no longer enjoys sex. She used to have a healthy libido and satisfying arousal and orgasm, but since starting the antidepressant, her sexual interest and pleasure have been low.

Although she’s afraid of sinking back into a depression without the medication, she’s willing to take the risk. If she were your patient, what alternatives would you suggest?

Sexual dysfunction affects an estimated 30% to 50% of patients on selective and nonselective SRIs, and some studies report rates as high as 70% to 80%.² Many patients stop taking these antidepressants prematurely, often because of sexual side effects.^3,4

Phosphodiesterase type 5 (PDE-5) inhibitors are well established as an effective treatment for erectile dysfunction,⁵ and randomized controlled trials (RCTs) have shown sildenafil to be effective in treating male SRI-induced sexual impairment.^6,7 For women, there has been no parallel evidence-based treatment.

Limited options, with little support

Typically, women who reported antidepressant-associated sexual disturbances have been offered options for which there was only weak evidence—dose changes or augmentation with another agent, switching to another antidepressant, or taking occasional drug holidays. A 2004 Cochrane review found that there were no RCTs involving dose changes or drug holidays.⁸ Among studies of the efficacy of switching to a different drug, nefazodone was the only agent whose use was supported by a double-blind RCT.⁹ Augmentation trials of a wide range of medications and supplements—including amantadine, bupropion, buspirone, granisetron, mirtazapine, olanzapine, ephedrine, ginkgo biloba, and yohimbine—yielded mixed results. Indeed, the research found that some were no better than placebo.

PDE-5 inhibitors for women? Inconclusive studies to date

Female sexual dysfunction is generally divided into 4 domains: disorders of desire, arousal, orgasm, or pain. Decreased desire and delayed or absent orgasm are the most common sexual side effects of SRI antidepressants in women.¹⁰ Several studies of PDE-5 inhibitors in this patient population have had positive results,^11-15 so there has been good reason to think that they might help this subset of women. However, all the studies were small and nonblinded, and therefore inconclusive—until now.

STUDY SUMMARY: Finally, a well-done RCT provides some answers

Investigators enrolled 98 premenopausal women from 7 US research centers in a double-blind randomized trial. To qualify, participants had to be diagnosed with major depression in remission, be taking a selective or nonselective SRI for >8 weeks, and be on a stable dose for >4 weeks. They also had to meet Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for substance-induced sexual dysfunction lasting >4 weeks, but have no history of sexual impairment independent of antidepressants. Finally, participants had to engage in some form of regular sexual activity—intercourse, oral sex, and masturbation all qualified—at least twice a month, and be willing to continue efforts to have sex at least once a week during the study. Women with other medical, psychiatric, or sexual problems were excluded, as were those who were pregnant, breastfeeding, or able to become pregnant and not using reliable contraception.

Participants were randomized to receive 50 mg of sildenafil (n=49) or a matching placebo tablet (n=49), which they were instructed to take 1 to 2 hours before sexual activity. The dose could be adjusted to 2 tablets (100 mg sildenafil) based on investigator assessment of the patient’s response to the initial dose. Participants and all study personnel were blinded to group assignment.

The primary outcome was change from baseline to end-point in the Clinical Global Impression Scale, a clinician-rated scale based on review of patient symptoms that was adapted to evaluate sexual function. Secondary outcomes were changes in 3 other sexual function scales, the Hamilton Rating Scale for Depression, and measured hormone levels.

Investigators followed the women for 8 weeks, measuring outcomes at 2, 4, and 8 weeks.

Sildenafil is better than placebo

Using an intention-to-treat analysis with the last measurement (2, 4, or 8 weeks) as the end-point, both the treatment and placebo groups experienced improvement in sexual function. The sildenafil group improved more than the placebo group. On the Clinical Global Impression Scale (1 to 7, with higher scores indicating worse sexual function), sildenafil users went from a mean of 4.8 to 2.8, while placebo users went from a mean of 4.7 to 3.6. The difference in mean change from baseline was 0.8 (95% confidence interval [CI] 0.6-1.0; P=.001). Using a more conservative analysis in which participants who did not return for the 8-week follow-up visit were assumed to have returned to baseline, the difference in mean change from baseline was smaller (0.6, 95% CI, 0.3-0.8; P=0.03) but still statistically significant.

Orgasmic function shows significant improvement

The sexual function scales used as secondary outcomes provided more detail about which types of sexual dysfunction benefited from sildenafil. On all 3 scales, orgasmic function significantly favored sildenafil over placebo. In the domains of desire, arousal, and pain disorders, small to moderate improvements were seen in both groups, with no statistically significant differences. One potential confounder—a difference in the course of participants’ underlying depression— was ruled out because depression scale results remained unchanged from baseline to endpoint in both groups.

Baseline levels of cortisone, estradiol, follicle-stimulating hormone, leuteinizing hormone, progesterone, prolactin, sex hormone-binding globulin, testosterone, thyroid-stimulating hormone, and thyroxine, were normal, with no differences between the sildenafil and placebo groups.

WHAT’S NEW: Women have an evidence-based option

Like their male counterparts, we can now offer women whose depression is effectively treated by SRI antidepressants—and who are motivated to stay sexually active despite medication-associated side effects—an effective pharmacotherapeutic treatment.

CAVEATS: Side effects and study funding are worth noting

Side effects. Significantly more participants in the sildenafil group vs the placebo group experienced the following side effects: headache (43% vs 27%), visual disturbance (14% vs 2%), dyspepsia (12% vs 0%), flushing (24% vs 0%), nasal congestion (37% vs 6%), and palpitations (8% vs 2%). Nausea was the only side effect that was more common in the placebo group, reported by only 2% of those in the intervention group but 16% of those on placebo.

No serious adverse events occurred, however, and the medication appears to have been well tolerated overall, despite relatively high rates of side effects. Participants in the intervention group used an average of 5 doses of sildenafil per 2-week interval, the same number as those in the placebo group.

Small treatment effect. The difference in response between sildenafil and placebo was not large: 0.8 points on a 7-point scale. But this difference is likely a clinically meaningful effect to the women with this problem.

Drug company funding. Pfizer, the maker of Viagra, funded this study through an investigator-initiated grant. Some researchers argue that female sexual dysfunction has been defined, or even invented, by drug companies seeking to create new markets for their products.¹⁶ This concern, coupled with the fact that this is the only double-blind randomized trial to show that sildenafil benefits women with antidepressant-associated sexual impairment, raises the question of whether this finding will be replicated in future trials.

We were reassured by the authors’ statement that Pfizer had no role in the study design, implementation, analysis, or manuscript preparation. And we know from clinical practice that women do suffer from SRI-induced sexual side effects, and sometimes stop taking much-needed antidepressants because the medication interferes with their ability to have a satisfying sex life. We believe this study was well done and offers a promising new therapy that deserves consideration. We hope that additional trials will follow and that investigators and journals will not hesitate to publish negative results.

Not for all women with sexual dysfunction

It’s a safe bet that these findings will be used to market sildenafil to women. It is therefore important for physicians and patients to keep in mind that this trial focused on a well-defined subset of women with sexual dysfunction: those on a stable dose of an SRI, with depression in remission, who were otherwise healthy and not pregnant, breastfeeding, or planning pregnancy, and who were motivated to be sexually active. Although this study does support the use of sildenafil for women in this subset, it does not support the use of PDE-5 inhibitors such as sildenafil for all women with sexual difficulties.

CHALLENGES TO IMPLEMENTATION: You have to ask!

Studies have repeatedly found that many women who experience sexual problems do not broach the subject with their doctors.¹⁷ So don’t wait for your female patients to bring it up. Sexual side effects are common enough with SRI antidepressants that all prescribers should mention the possibility in advance. Tell patients to let you know if they develop medication-related sexual dysfunction, and reassure them that there are treatments that can help.

Acknowledgment

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.

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 34-year-old woman comes to your office and asks to be taken off the paroxetine you prescribed for her 4 months ago. The medication is working well; her depression has been in remission for at least 12 weeks. But she no longer enjoys sex. She used to have a healthy libido and satisfying arousal and orgasm, but since starting the antidepressant, her sexual interest and pleasure have been low.

Although she’s afraid of sinking back into a depression without the medication, she’s willing to take the risk. If she were your patient, what alternatives would you suggest?

Sexual dysfunction affects an estimated 30% to 50% of patients on selective and nonselective SRIs, and some studies report rates as high as 70% to 80%.² Many patients stop taking these antidepressants prematurely, often because of sexual side effects.^3,4

Phosphodiesterase type 5 (PDE-5) inhibitors are well established as an effective treatment for erectile dysfunction,⁵ and randomized controlled trials (RCTs) have shown sildenafil to be effective in treating male SRI-induced sexual impairment.^6,7 For women, there has been no parallel evidence-based treatment.

Limited options, with little support

Typically, women who reported antidepressant-associated sexual disturbances have been offered options for which there was only weak evidence—dose changes or augmentation with another agent, switching to another antidepressant, or taking occasional drug holidays. A 2004 Cochrane review found that there were no RCTs involving dose changes or drug holidays.⁸ Among studies of the efficacy of switching to a different drug, nefazodone was the only agent whose use was supported by a double-blind RCT.⁹ Augmentation trials of a wide range of medications and supplements—including amantadine, bupropion, buspirone, granisetron, mirtazapine, olanzapine, ephedrine, ginkgo biloba, and yohimbine—yielded mixed results. Indeed, the research found that some were no better than placebo.

PDE-5 inhibitors for women? Inconclusive studies to date

Female sexual dysfunction is generally divided into 4 domains: disorders of desire, arousal, orgasm, or pain. Decreased desire and delayed or absent orgasm are the most common sexual side effects of SRI antidepressants in women.¹⁰ Several studies of PDE-5 inhibitors in this patient population have had positive results,^11-15 so there has been good reason to think that they might help this subset of women. However, all the studies were small and nonblinded, and therefore inconclusive—until now.

STUDY SUMMARY: Finally, a well-done RCT provides some answers

Investigators enrolled 98 premenopausal women from 7 US research centers in a double-blind randomized trial. To qualify, participants had to be diagnosed with major depression in remission, be taking a selective or nonselective SRI for >8 weeks, and be on a stable dose for >4 weeks. They also had to meet Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for substance-induced sexual dysfunction lasting >4 weeks, but have no history of sexual impairment independent of antidepressants. Finally, participants had to engage in some form of regular sexual activity—intercourse, oral sex, and masturbation all qualified—at least twice a month, and be willing to continue efforts to have sex at least once a week during the study. Women with other medical, psychiatric, or sexual problems were excluded, as were those who were pregnant, breastfeeding, or able to become pregnant and not using reliable contraception.

Participants were randomized to receive 50 mg of sildenafil (n=49) or a matching placebo tablet (n=49), which they were instructed to take 1 to 2 hours before sexual activity. The dose could be adjusted to 2 tablets (100 mg sildenafil) based on investigator assessment of the patient’s response to the initial dose. Participants and all study personnel were blinded to group assignment.

The primary outcome was change from baseline to end-point in the Clinical Global Impression Scale, a clinician-rated scale based on review of patient symptoms that was adapted to evaluate sexual function. Secondary outcomes were changes in 3 other sexual function scales, the Hamilton Rating Scale for Depression, and measured hormone levels.

Investigators followed the women for 8 weeks, measuring outcomes at 2, 4, and 8 weeks.

Sildenafil is better than placebo

Using an intention-to-treat analysis with the last measurement (2, 4, or 8 weeks) as the end-point, both the treatment and placebo groups experienced improvement in sexual function. The sildenafil group improved more than the placebo group. On the Clinical Global Impression Scale (1 to 7, with higher scores indicating worse sexual function), sildenafil users went from a mean of 4.8 to 2.8, while placebo users went from a mean of 4.7 to 3.6. The difference in mean change from baseline was 0.8 (95% confidence interval [CI] 0.6-1.0; P=.001). Using a more conservative analysis in which participants who did not return for the 8-week follow-up visit were assumed to have returned to baseline, the difference in mean change from baseline was smaller (0.6, 95% CI, 0.3-0.8; P=0.03) but still statistically significant.

Orgasmic function shows significant improvement

The sexual function scales used as secondary outcomes provided more detail about which types of sexual dysfunction benefited from sildenafil. On all 3 scales, orgasmic function significantly favored sildenafil over placebo. In the domains of desire, arousal, and pain disorders, small to moderate improvements were seen in both groups, with no statistically significant differences. One potential confounder—a difference in the course of participants’ underlying depression— was ruled out because depression scale results remained unchanged from baseline to endpoint in both groups.

Baseline levels of cortisone, estradiol, follicle-stimulating hormone, leuteinizing hormone, progesterone, prolactin, sex hormone-binding globulin, testosterone, thyroid-stimulating hormone, and thyroxine, were normal, with no differences between the sildenafil and placebo groups.

WHAT’S NEW: Women have an evidence-based option

Like their male counterparts, we can now offer women whose depression is effectively treated by SRI antidepressants—and who are motivated to stay sexually active despite medication-associated side effects—an effective pharmacotherapeutic treatment.

CAVEATS: Side effects and study funding are worth noting

Side effects. Significantly more participants in the sildenafil group vs the placebo group experienced the following side effects: headache (43% vs 27%), visual disturbance (14% vs 2%), dyspepsia (12% vs 0%), flushing (24% vs 0%), nasal congestion (37% vs 6%), and palpitations (8% vs 2%). Nausea was the only side effect that was more common in the placebo group, reported by only 2% of those in the intervention group but 16% of those on placebo.

No serious adverse events occurred, however, and the medication appears to have been well tolerated overall, despite relatively high rates of side effects. Participants in the intervention group used an average of 5 doses of sildenafil per 2-week interval, the same number as those in the placebo group.

Small treatment effect. The difference in response between sildenafil and placebo was not large: 0.8 points on a 7-point scale. But this difference is likely a clinically meaningful effect to the women with this problem.

Drug company funding. Pfizer, the maker of Viagra, funded this study through an investigator-initiated grant. Some researchers argue that female sexual dysfunction has been defined, or even invented, by drug companies seeking to create new markets for their products.¹⁶ This concern, coupled with the fact that this is the only double-blind randomized trial to show that sildenafil benefits women with antidepressant-associated sexual impairment, raises the question of whether this finding will be replicated in future trials.

We were reassured by the authors’ statement that Pfizer had no role in the study design, implementation, analysis, or manuscript preparation. And we know from clinical practice that women do suffer from SRI-induced sexual side effects, and sometimes stop taking much-needed antidepressants because the medication interferes with their ability to have a satisfying sex life. We believe this study was well done and offers a promising new therapy that deserves consideration. We hope that additional trials will follow and that investigators and journals will not hesitate to publish negative results.

Not for all women with sexual dysfunction

It’s a safe bet that these findings will be used to market sildenafil to women. It is therefore important for physicians and patients to keep in mind that this trial focused on a well-defined subset of women with sexual dysfunction: those on a stable dose of an SRI, with depression in remission, who were otherwise healthy and not pregnant, breastfeeding, or planning pregnancy, and who were motivated to be sexually active. Although this study does support the use of sildenafil for women in this subset, it does not support the use of PDE-5 inhibitors such as sildenafil for all women with sexual difficulties.

CHALLENGES TO IMPLEMENTATION: You have to ask!

Studies have repeatedly found that many women who experience sexual problems do not broach the subject with their doctors.¹⁷ So don’t wait for your female patients to bring it up. Sexual side effects are common enough with SRI antidepressants that all prescribers should mention the possibility in advance. Tell patients to let you know if they develop medication-related sexual dysfunction, and reassure them that there are treatments that can help.

Acknowledgment

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.

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.