Clinical Inquiries

Evidence summary

Acne vulgaris is the most common cutaneous disorder, affecting about 45 million people in the United States. Five to 6 million acne-related visits are made to physicians in outpatient offices each year.¹

For mild noninflammatory (come-donal) acne, the preferred option is monotherapy with topical retinoids. Randomized controlled trials (RCTs) have proven the efficacy of tretinoin, an older retinoid for comedonal acne.² In one RCT, patients were randomly assigned to 1 of 3 treatment groups, each having 33 enrollees: patients in the first group received 0.1% tazarotene gel as twice daily application; the second group received 0.1% tazarotene gel in the evening and vehicle gel in the morning; the third group received vehicle gel twice daily. By 12 weeks, the first and second groups achieved significantly greater improvement in acne than the third group, based on mean percentage reduction in noninflammatory lesions (46% and 41% vs 2%; P=.002) and inflammatory lesions (38% and 34% vs 9%; P=.01).³ Another 12-week RCT of 237 patients with mild to moderate acne demonstrated superior efficacy with 0.1% adapalene cream over placebo (P<.05).⁴ While most studies did not compare the use of one retinoid vs another, a recent meta-analysis of placebo-controlled trials concluded that topical tazarotene is more effective in treating mild comedonal acne than adapalene or tretinoin, although it may be more likely to cause skin irritation.^6,7

A systematic review evaluating the evidence for treatment of acne found that combining topical antibiotics with topical retinoids or benzoyl peroxide is effective for moderate noninflammatory (come-donal) and mild to moderate inflammatory (papulopustular) acne.⁷ Because of its antibacterial and anti-comedogenic properties, benzoyl peroxide is preferred to retinoids for inflammatory acne. Another benefit of using benzoyl peroxide with antibiotic cream is its potential to reduce antibiotic-associated resistance to Propionibacterium acnes.^7,8

No comparative trials or meta-analyses compare efficacy of different combination therapies. A recent narrative review of clinical trials concluded that clindamycin plus benzoyl peroxide was more effective in reducing inflammatory lesions than monotherapy with either agent alone, and was similar in efficacy to benzoyl peroxide/erythromycin combination.⁸ Similarly, combination therapy with clindamycin and adapalene was superior to clindamycin alone in improving mild to moderate acne.⁹ Both 1% clindamycin and 2% erythromycin were comparable in reducing inflammatory and noninflammatory lesions for patients with moderate acne.¹⁰

Studies are ongoing for topical tetracycline, topical isotretinoin, and light and laser therapy in treatment of mild to moderate acne.

Recommendations from others

An expert review stated that treatment of acne should be individualized for best results.⁷ A report from the Global Alliance to Improve Outcomes in Acne states that topical retinoids are appropriate first-line therapy for all forms of acne and should be combined with topical antimicrobial therapy when inflammatory lesions are present.¹¹

Evidence summary

Acne vulgaris is the most common cutaneous disorder, affecting about 45 million people in the United States. Five to 6 million acne-related visits are made to physicians in outpatient offices each year.¹

For mild noninflammatory (come-donal) acne, the preferred option is monotherapy with topical retinoids. Randomized controlled trials (RCTs) have proven the efficacy of tretinoin, an older retinoid for comedonal acne.² In one RCT, patients were randomly assigned to 1 of 3 treatment groups, each having 33 enrollees: patients in the first group received 0.1% tazarotene gel as twice daily application; the second group received 0.1% tazarotene gel in the evening and vehicle gel in the morning; the third group received vehicle gel twice daily. By 12 weeks, the first and second groups achieved significantly greater improvement in acne than the third group, based on mean percentage reduction in noninflammatory lesions (46% and 41% vs 2%; P=.002) and inflammatory lesions (38% and 34% vs 9%; P=.01).³ Another 12-week RCT of 237 patients with mild to moderate acne demonstrated superior efficacy with 0.1% adapalene cream over placebo (P<.05).⁴ While most studies did not compare the use of one retinoid vs another, a recent meta-analysis of placebo-controlled trials concluded that topical tazarotene is more effective in treating mild comedonal acne than adapalene or tretinoin, although it may be more likely to cause skin irritation.^6,7

A systematic review evaluating the evidence for treatment of acne found that combining topical antibiotics with topical retinoids or benzoyl peroxide is effective for moderate noninflammatory (come-donal) and mild to moderate inflammatory (papulopustular) acne.⁷ Because of its antibacterial and anti-comedogenic properties, benzoyl peroxide is preferred to retinoids for inflammatory acne. Another benefit of using benzoyl peroxide with antibiotic cream is its potential to reduce antibiotic-associated resistance to Propionibacterium acnes.^7,8

No comparative trials or meta-analyses compare efficacy of different combination therapies. A recent narrative review of clinical trials concluded that clindamycin plus benzoyl peroxide was more effective in reducing inflammatory lesions than monotherapy with either agent alone, and was similar in efficacy to benzoyl peroxide/erythromycin combination.⁸ Similarly, combination therapy with clindamycin and adapalene was superior to clindamycin alone in improving mild to moderate acne.⁹ Both 1% clindamycin and 2% erythromycin were comparable in reducing inflammatory and noninflammatory lesions for patients with moderate acne.¹⁰

Studies are ongoing for topical tetracycline, topical isotretinoin, and light and laser therapy in treatment of mild to moderate acne.

Recommendations from others

An expert review stated that treatment of acne should be individualized for best results.⁷ A report from the Global Alliance to Improve Outcomes in Acne states that topical retinoids are appropriate first-line therapy for all forms of acne and should be combined with topical antimicrobial therapy when inflammatory lesions are present.¹¹

Evidence summary

Acne vulgaris is the most common cutaneous disorder, affecting about 45 million people in the United States. Five to 6 million acne-related visits are made to physicians in outpatient offices each year.¹

For mild noninflammatory (come-donal) acne, the preferred option is monotherapy with topical retinoids. Randomized controlled trials (RCTs) have proven the efficacy of tretinoin, an older retinoid for comedonal acne.² In one RCT, patients were randomly assigned to 1 of 3 treatment groups, each having 33 enrollees: patients in the first group received 0.1% tazarotene gel as twice daily application; the second group received 0.1% tazarotene gel in the evening and vehicle gel in the morning; the third group received vehicle gel twice daily. By 12 weeks, the first and second groups achieved significantly greater improvement in acne than the third group, based on mean percentage reduction in noninflammatory lesions (46% and 41% vs 2%; P=.002) and inflammatory lesions (38% and 34% vs 9%; P=.01).³ Another 12-week RCT of 237 patients with mild to moderate acne demonstrated superior efficacy with 0.1% adapalene cream over placebo (P<.05).⁴ While most studies did not compare the use of one retinoid vs another, a recent meta-analysis of placebo-controlled trials concluded that topical tazarotene is more effective in treating mild comedonal acne than adapalene or tretinoin, although it may be more likely to cause skin irritation.^6,7

A systematic review evaluating the evidence for treatment of acne found that combining topical antibiotics with topical retinoids or benzoyl peroxide is effective for moderate noninflammatory (come-donal) and mild to moderate inflammatory (papulopustular) acne.⁷ Because of its antibacterial and anti-comedogenic properties, benzoyl peroxide is preferred to retinoids for inflammatory acne. Another benefit of using benzoyl peroxide with antibiotic cream is its potential to reduce antibiotic-associated resistance to Propionibacterium acnes.^7,8

No comparative trials or meta-analyses compare efficacy of different combination therapies. A recent narrative review of clinical trials concluded that clindamycin plus benzoyl peroxide was more effective in reducing inflammatory lesions than monotherapy with either agent alone, and was similar in efficacy to benzoyl peroxide/erythromycin combination.⁸ Similarly, combination therapy with clindamycin and adapalene was superior to clindamycin alone in improving mild to moderate acne.⁹ Both 1% clindamycin and 2% erythromycin were comparable in reducing inflammatory and noninflammatory lesions for patients with moderate acne.¹⁰

Studies are ongoing for topical tetracycline, topical isotretinoin, and light and laser therapy in treatment of mild to moderate acne.

Recommendations from others

An expert review stated that treatment of acne should be individualized for best results.⁷ A report from the Global Alliance to Improve Outcomes in Acne states that topical retinoids are appropriate first-line therapy for all forms of acne and should be combined with topical antimicrobial therapy when inflammatory lesions are present.¹¹

Evidence summary

Healthy lifestyles are an important part of both prevention and management of hypertension. These changes include maintenance of normal body weight, regular aerobic exercise, dietary salt reduction, alcohol consumption reduction, and consumption of diets rich in potassium, fruits, and vegetables. These recommendations have been reviewed in recent meta-analyses (TABLE).

Lifestyle changes that have not shown any significant effect on blood pressure or that are still under review include dietary omega-3 fatty acid supplementation and antioxidant supplementation.¹⁰

TABLE
Summary of recommendations

Recommendations from others

The National High Blood Pressure Education Program recommends the following for primary prevention of hypertension:¹¹

• Maintain normal body weight for adults
• Reduce dietary sodium intake to no more than 100 mmol/d
• Engage in regular aerobic physical activity
• Limit alcohol consumption to 30 mL ethanol per day for men, and 15 mL ethanol per day for women or lighter persons
• Maintain adequate intake of dietary potassium (>90 mmol/d)
• Consume a diet rich in fruits, vegetables, and low-fat dairy, with reduced content of saturated and total fat.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure agrees with the recommendations in the TABLE.¹²

Evidence summary

Healthy lifestyles are an important part of both prevention and management of hypertension. These changes include maintenance of normal body weight, regular aerobic exercise, dietary salt reduction, alcohol consumption reduction, and consumption of diets rich in potassium, fruits, and vegetables. These recommendations have been reviewed in recent meta-analyses (TABLE).

Lifestyle changes that have not shown any significant effect on blood pressure or that are still under review include dietary omega-3 fatty acid supplementation and antioxidant supplementation.¹⁰

TABLE
Summary of recommendations

Recommendations from others

The National High Blood Pressure Education Program recommends the following for primary prevention of hypertension:¹¹

• Maintain normal body weight for adults
• Reduce dietary sodium intake to no more than 100 mmol/d
• Engage in regular aerobic physical activity
• Limit alcohol consumption to 30 mL ethanol per day for men, and 15 mL ethanol per day for women or lighter persons
• Maintain adequate intake of dietary potassium (>90 mmol/d)
• Consume a diet rich in fruits, vegetables, and low-fat dairy, with reduced content of saturated and total fat.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure agrees with the recommendations in the TABLE.¹²

Evidence summary

Healthy lifestyles are an important part of both prevention and management of hypertension. These changes include maintenance of normal body weight, regular aerobic exercise, dietary salt reduction, alcohol consumption reduction, and consumption of diets rich in potassium, fruits, and vegetables. These recommendations have been reviewed in recent meta-analyses (TABLE).

Lifestyle changes that have not shown any significant effect on blood pressure or that are still under review include dietary omega-3 fatty acid supplementation and antioxidant supplementation.¹⁰

TABLE
Summary of recommendations

Recommendations from others

The National High Blood Pressure Education Program recommends the following for primary prevention of hypertension:¹¹

• Maintain normal body weight for adults
• Reduce dietary sodium intake to no more than 100 mmol/d
• Engage in regular aerobic physical activity
• Limit alcohol consumption to 30 mL ethanol per day for men, and 15 mL ethanol per day for women or lighter persons
• Maintain adequate intake of dietary potassium (>90 mmol/d)
• Consume a diet rich in fruits, vegetables, and low-fat dairy, with reduced content of saturated and total fat.

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure agrees with the recommendations in the TABLE.¹²

Evidence summary

No studies specifically examine the risk of adverse outcomes for women who have mild elevations in blood pressure as a result of taking OCs. However, for the general population cardiovascular risk increases 30% for each 10 mm Hg rise in systolic pressure.¹

A prospective cohort study found an increased incidence of new hypertension developing among women taking OCs. The study, conducted in the US, included 68,297 female nurses aged 25 to 42 years without a previous diagnosis of hypertension, diabetes, coronary heart disease, stroke, or cancer, who were followed for 4 years. Women were excluded from the study if they had not had a physical exam in the last 2 years or were taking antihypertensive medication at study inception. The nurses self-reported their blood pressure readings via questionnaire; medical records were sampled to validate the accuracy of self-reports. After adjusting for risk factors, current oral contraceptive use increased the risk of developing hypertension (relative risk [RR]=1.8; 95% confidence interval [CI], 1.5–2.3; corresponding to 41.5 new cases of hypertension per 10,000 person-years).²

A systematic review of 8 case control studies (with 4907 cases and 13,443 controls) found an increased risk of stroke and MI among hypertensive women taking combined type OCs vs those not taking OCs. Women with hypertension aged 20 to 24 years had an estimated CV event risk of 312 per million woman-years while taking OCs vs 134 per million woman-years not taking OCs. Among hypertensive women aged 40 to 44 years, the estimated risks were 1213 vs 529 per million woman-years, respectively. Primary endpoints varied across the studies and statistical significance was not given.³

Three studies showed that blood pressure elevations due to taking oral contraceptives returned to baseline with discontinuation of the medication. A prospective cohort study followed 13,358 women who were neither pregnant nor postpartum between the ages of 15 and 60. Women who either initiated or resumed using OCs experienced a statistically significant rise of about 4 mm Hg in the systolic pressure and 1 mm Hg in the diastolic pressure. Women who stopped using OCs experienced significant decreases in both systolic and diastolic components (about 5 mm Hg and 1.5 mm Hg, respectively).¹

Similarly, a survey study of 461 women attending family planning clinics found that mean blood pressures were significantly higher for those taking OCs than for those using nonhormonal contraception. Elevated blood pressures correlated with duration of current use of OCs but returned to normal soon after stopping OCs. The mean pressures of those who had stopped OCs more than a month were similar to those of women who had never taken an OC and significantly lower than those of women who were currently taking OCs.⁴

Finally, a prospective study which followed 32 women who had taken combined OCs for 1 to 3 years and then stopped found that blood pressures returned to pretreatment levels at 3 months. Systolic pressure fell by 9.7 mm Hg and diastolic by 2.9 mm Hg compared with measurements made 1 month before stopping. No cardiovascular complications were reported among women during this study.⁵

Recommendations from others

The American College of Obstetricians and Gynecologists says that women with well-controlled and monitored hypertension aged 35 years and younger are appropriate candidates for a trial of combination OCs, provided they are otherwise healthy, have no evidence of end-organ vascular disease, and do not smoke cigarettes.⁶ If blood pressure remains well controlled with careful monitoring several months after initiating OCs, use can be continued.

Evidence summary

No studies specifically examine the risk of adverse outcomes for women who have mild elevations in blood pressure as a result of taking OCs. However, for the general population cardiovascular risk increases 30% for each 10 mm Hg rise in systolic pressure.¹

A prospective cohort study found an increased incidence of new hypertension developing among women taking OCs. The study, conducted in the US, included 68,297 female nurses aged 25 to 42 years without a previous diagnosis of hypertension, diabetes, coronary heart disease, stroke, or cancer, who were followed for 4 years. Women were excluded from the study if they had not had a physical exam in the last 2 years or were taking antihypertensive medication at study inception. The nurses self-reported their blood pressure readings via questionnaire; medical records were sampled to validate the accuracy of self-reports. After adjusting for risk factors, current oral contraceptive use increased the risk of developing hypertension (relative risk [RR]=1.8; 95% confidence interval [CI], 1.5–2.3; corresponding to 41.5 new cases of hypertension per 10,000 person-years).²

A systematic review of 8 case control studies (with 4907 cases and 13,443 controls) found an increased risk of stroke and MI among hypertensive women taking combined type OCs vs those not taking OCs. Women with hypertension aged 20 to 24 years had an estimated CV event risk of 312 per million woman-years while taking OCs vs 134 per million woman-years not taking OCs. Among hypertensive women aged 40 to 44 years, the estimated risks were 1213 vs 529 per million woman-years, respectively. Primary endpoints varied across the studies and statistical significance was not given.³

Three studies showed that blood pressure elevations due to taking oral contraceptives returned to baseline with discontinuation of the medication. A prospective cohort study followed 13,358 women who were neither pregnant nor postpartum between the ages of 15 and 60. Women who either initiated or resumed using OCs experienced a statistically significant rise of about 4 mm Hg in the systolic pressure and 1 mm Hg in the diastolic pressure. Women who stopped using OCs experienced significant decreases in both systolic and diastolic components (about 5 mm Hg and 1.5 mm Hg, respectively).¹

Similarly, a survey study of 461 women attending family planning clinics found that mean blood pressures were significantly higher for those taking OCs than for those using nonhormonal contraception. Elevated blood pressures correlated with duration of current use of OCs but returned to normal soon after stopping OCs. The mean pressures of those who had stopped OCs more than a month were similar to those of women who had never taken an OC and significantly lower than those of women who were currently taking OCs.⁴

Finally, a prospective study which followed 32 women who had taken combined OCs for 1 to 3 years and then stopped found that blood pressures returned to pretreatment levels at 3 months. Systolic pressure fell by 9.7 mm Hg and diastolic by 2.9 mm Hg compared with measurements made 1 month before stopping. No cardiovascular complications were reported among women during this study.⁵

Recommendations from others

The American College of Obstetricians and Gynecologists says that women with well-controlled and monitored hypertension aged 35 years and younger are appropriate candidates for a trial of combination OCs, provided they are otherwise healthy, have no evidence of end-organ vascular disease, and do not smoke cigarettes.⁶ If blood pressure remains well controlled with careful monitoring several months after initiating OCs, use can be continued.

Evidence summary

No studies specifically examine the risk of adverse outcomes for women who have mild elevations in blood pressure as a result of taking OCs. However, for the general population cardiovascular risk increases 30% for each 10 mm Hg rise in systolic pressure.¹

A prospective cohort study found an increased incidence of new hypertension developing among women taking OCs. The study, conducted in the US, included 68,297 female nurses aged 25 to 42 years without a previous diagnosis of hypertension, diabetes, coronary heart disease, stroke, or cancer, who were followed for 4 years. Women were excluded from the study if they had not had a physical exam in the last 2 years or were taking antihypertensive medication at study inception. The nurses self-reported their blood pressure readings via questionnaire; medical records were sampled to validate the accuracy of self-reports. After adjusting for risk factors, current oral contraceptive use increased the risk of developing hypertension (relative risk [RR]=1.8; 95% confidence interval [CI], 1.5–2.3; corresponding to 41.5 new cases of hypertension per 10,000 person-years).²

A systematic review of 8 case control studies (with 4907 cases and 13,443 controls) found an increased risk of stroke and MI among hypertensive women taking combined type OCs vs those not taking OCs. Women with hypertension aged 20 to 24 years had an estimated CV event risk of 312 per million woman-years while taking OCs vs 134 per million woman-years not taking OCs. Among hypertensive women aged 40 to 44 years, the estimated risks were 1213 vs 529 per million woman-years, respectively. Primary endpoints varied across the studies and statistical significance was not given.³

Three studies showed that blood pressure elevations due to taking oral contraceptives returned to baseline with discontinuation of the medication. A prospective cohort study followed 13,358 women who were neither pregnant nor postpartum between the ages of 15 and 60. Women who either initiated or resumed using OCs experienced a statistically significant rise of about 4 mm Hg in the systolic pressure and 1 mm Hg in the diastolic pressure. Women who stopped using OCs experienced significant decreases in both systolic and diastolic components (about 5 mm Hg and 1.5 mm Hg, respectively).¹

Similarly, a survey study of 461 women attending family planning clinics found that mean blood pressures were significantly higher for those taking OCs than for those using nonhormonal contraception. Elevated blood pressures correlated with duration of current use of OCs but returned to normal soon after stopping OCs. The mean pressures of those who had stopped OCs more than a month were similar to those of women who had never taken an OC and significantly lower than those of women who were currently taking OCs.⁴

Finally, a prospective study which followed 32 women who had taken combined OCs for 1 to 3 years and then stopped found that blood pressures returned to pretreatment levels at 3 months. Systolic pressure fell by 9.7 mm Hg and diastolic by 2.9 mm Hg compared with measurements made 1 month before stopping. No cardiovascular complications were reported among women during this study.⁵

Recommendations from others

The American College of Obstetricians and Gynecologists says that women with well-controlled and monitored hypertension aged 35 years and younger are appropriate candidates for a trial of combination OCs, provided they are otherwise healthy, have no evidence of end-organ vascular disease, and do not smoke cigarettes.⁶ If blood pressure remains well controlled with careful monitoring several months after initiating OCs, use can be continued.

Evidence summary

Induction of labor is a viable therapeutic option when the benefits of timely delivery outweigh the risks of unnecessary cesarean section or prematurity. Two large retrospective studies support the concept that cesarean section rates and admissions to neonatal intensive care units are higher with elective induction as opposed to expectant management (TABLE).^1,2 A large population-based study suggests that the higher cesarean section rates in elective induction is present only among nulliparous women; in multiparous women, the rate is the same as expectant management.³ Contrasting these results are those of a large systematic review, which found lower cesarean section rates in electively induced women. Two more recent studies, a retrospective cohort study⁴ and a randomized controlled trial,⁵ found a much lower incidence of cesarean section and operative vaginal deliveries among induced vs expectantly managed women at term.

TABLE
Summary of evidence regarding induction of labor

Recommendations from others

A 1999 American College of Obstetricians and Gynecologists (ACOG) practice bulletin states that labor may be induced for logistic reasons such as psychosocial factors and distance from hospital, as long as 1 of these 4 criteria is met: (1) fetal heart tones have been documented for 20 weeks by nonelectronic fetoscope or for 30 weeks by Doppler; (2) it has been 36 weeks since a positive serum or urine human chorionic gonadotropin pregnancy test was performed; (3) ultrasound measurement of crown-rump length, obtained at 6 to 12 weeks, supports a gestational age of at least 39 weeks; (4) ultrasound obtained at 13 to 20 weeks confirms the gestational age of at least 39 weeks determined by clinical history and physical examination. The ACOG recommendation (which dates back to 1989) is for induction of low-risk pregnancy at the 43rd week of gestation.⁷

The Royal College of Obstetricians and Gynaecologists recommends that women with uncomplicated pregnancies be offered induction of labor beyond 41 weeks.⁸ The Department of Obstetrics and Gynecology and Reproductive Biology at Harvard Medical School recommends routine induction of labor be recommended at 41 weeks’ gestation.⁹

Evidence summary

Induction of labor is a viable therapeutic option when the benefits of timely delivery outweigh the risks of unnecessary cesarean section or prematurity. Two large retrospective studies support the concept that cesarean section rates and admissions to neonatal intensive care units are higher with elective induction as opposed to expectant management (TABLE).^1,2 A large population-based study suggests that the higher cesarean section rates in elective induction is present only among nulliparous women; in multiparous women, the rate is the same as expectant management.³ Contrasting these results are those of a large systematic review, which found lower cesarean section rates in electively induced women. Two more recent studies, a retrospective cohort study⁴ and a randomized controlled trial,⁵ found a much lower incidence of cesarean section and operative vaginal deliveries among induced vs expectantly managed women at term.

TABLE
Summary of evidence regarding induction of labor

Recommendations from others

A 1999 American College of Obstetricians and Gynecologists (ACOG) practice bulletin states that labor may be induced for logistic reasons such as psychosocial factors and distance from hospital, as long as 1 of these 4 criteria is met: (1) fetal heart tones have been documented for 20 weeks by nonelectronic fetoscope or for 30 weeks by Doppler; (2) it has been 36 weeks since a positive serum or urine human chorionic gonadotropin pregnancy test was performed; (3) ultrasound measurement of crown-rump length, obtained at 6 to 12 weeks, supports a gestational age of at least 39 weeks; (4) ultrasound obtained at 13 to 20 weeks confirms the gestational age of at least 39 weeks determined by clinical history and physical examination. The ACOG recommendation (which dates back to 1989) is for induction of low-risk pregnancy at the 43rd week of gestation.⁷

The Royal College of Obstetricians and Gynaecologists recommends that women with uncomplicated pregnancies be offered induction of labor beyond 41 weeks.⁸ The Department of Obstetrics and Gynecology and Reproductive Biology at Harvard Medical School recommends routine induction of labor be recommended at 41 weeks’ gestation.⁹

Evidence summary

Induction of labor is a viable therapeutic option when the benefits of timely delivery outweigh the risks of unnecessary cesarean section or prematurity. Two large retrospective studies support the concept that cesarean section rates and admissions to neonatal intensive care units are higher with elective induction as opposed to expectant management (TABLE).^1,2 A large population-based study suggests that the higher cesarean section rates in elective induction is present only among nulliparous women; in multiparous women, the rate is the same as expectant management.³ Contrasting these results are those of a large systematic review, which found lower cesarean section rates in electively induced women. Two more recent studies, a retrospective cohort study⁴ and a randomized controlled trial,⁵ found a much lower incidence of cesarean section and operative vaginal deliveries among induced vs expectantly managed women at term.

TABLE
Summary of evidence regarding induction of labor

Recommendations from others

A 1999 American College of Obstetricians and Gynecologists (ACOG) practice bulletin states that labor may be induced for logistic reasons such as psychosocial factors and distance from hospital, as long as 1 of these 4 criteria is met: (1) fetal heart tones have been documented for 20 weeks by nonelectronic fetoscope or for 30 weeks by Doppler; (2) it has been 36 weeks since a positive serum or urine human chorionic gonadotropin pregnancy test was performed; (3) ultrasound measurement of crown-rump length, obtained at 6 to 12 weeks, supports a gestational age of at least 39 weeks; (4) ultrasound obtained at 13 to 20 weeks confirms the gestational age of at least 39 weeks determined by clinical history and physical examination. The ACOG recommendation (which dates back to 1989) is for induction of low-risk pregnancy at the 43rd week of gestation.⁷

The Royal College of Obstetricians and Gynaecologists recommends that women with uncomplicated pregnancies be offered induction of labor beyond 41 weeks.⁸ The Department of Obstetrics and Gynecology and Reproductive Biology at Harvard Medical School recommends routine induction of labor be recommended at 41 weeks’ gestation.⁹

Evidence summary

No studies specifically evaluate effective treatments for ODD (distinguished by chronic argumentativeness and refusal to comply with adult requests) for adolescent patients. However, there are treatment studies of younger children with ODD and studies of adolescents with the more disruptive behavior problem of conduct disorder (distinguished by a persistent pattern of violating other’s rights, aggression, and illegal acts).

A Clinical Inquiry summarized 8 well-done systematic reviews of ODD treatments of preadolescent children and found improved behavior with parenting interventions and behavioral therapy.¹ Each of the systematic reviews assessed multiple randomized controlled trials (RCTs) using a variety of parenting and behavioral therapy interventions. The most rigorous systematic review (which included 16 RCTs), compared group-based parenting skills training with untreated wait-list controls and found decreased aggression, noncompliance, and temper tantrums by children aged 3 to 10 years (total number of subjects not given) by an average effect size of 0.6 to 2.9. (Effect size is the difference between the means of the experimental and control groups expressed in standard deviations. An effect size of 0.2 is considered small, 0.5 is medium, and 0.8 is moderate to large.) Behavioral therapy (cognitive-behavioral therapy, social problem-solving skills training, parent management training), comprising 12 to 25 sessions with either the child alone or with teachers or parents, decreased disruptive or aggressive behaviors by 20% to 30%.

A 2-year case-control study² of 158 self-referred families with young adolescents (11 to 14 years old) without a formal ODD diagnosis but with reported problem behaviors (defined as smoking, negative engagement in family problem solving, and parental ratings of unpleasant events) found significant improvements (P<.01) with parent-only, teen-only, and parent-teen behavioral interventions for negative engagement behaviors (average of 30% reduction in scores), and with parent and teen interventions for unpleasant events (average of 9% reduction in scores). Interventions comprised 12 weekly 90-minute sessions, with the parent-only group targeting family management practices and communication skills, the teen-only group targeting adolescent self-regulation and pro-social behavior, and the parent-teen group following a structured curriculum.

A meta-analysis³ of 8 RCTs (with a total of 749 children) of various behavioral treatments for conduct disorder and juvenile delinquency among children aged 10 to 17 years found significant reductions in rearrest rates (relative risk [RR]=0.66; 95% confidence interval [CI], 0.44–0.98; number needed to treat [NNT] to prevent 1 rearrest=3.7) and time spent in institutions (mean difference, 51 days) with family and parenting interventions (comprising 1 to 6 months of individual and group parenting training, short and long-term family therapy, and individual and group adolescent interventions).

ODD comorbid with other psychiatric conditions

Approximately half to two-thirds of adolescents with ODD also have ADHD.⁴ A meta-analysis⁵ evaluated 28 studies of stimulant medication (methylphenidate, amphetamine, or pemoline) for children with comorbid ADHD and ODD. A total of 683 patients aged 8 to 18 years were included. Stimulants reduced aggression-related behaviors in these children by an effect size of 0.84 for overt aggression and 0.69 for covert aggression. Stimulants typically reduce aggressive behaviors by similar effect sizes when prescribed for children with ADD alone. The study groups did not separate children with ADHD and ODD from those with ADHD and conduct disorder; they also grouped adolescents together with younger children.

An RCT⁶ of different doses of atomoxetine (Strattera) treatment vs placebo for children ages 8 to 18 (mean age=11) with ADHD alone (N=178) and children with both ADHD and ODD (N=115) found significant effect sizes for atomoxetine in both groups. Two dosages of atomoxetine (1.2 and 1.8 mg/kg/d) produced equivalent effect sizes in the ADHD-only group (0.55 and 0.56); however, the higher dosage had a greater effect size (0.49 vs 0.69) in the group with ODD comorbid with ADHD.

A double-blind crossover RCT⁷ evaluated divalproex (Depakote) vs placebo for 20 children (aged 10 to 18 years) with explosive temper and mood lability who also met DSM-IV criteria for either ODD or conduct disorder. Patients with significant medical problems, such as bipolar disorder, major depression, or mental retardation, were excluded. Divalproex significantly (P=.003) reduced aggressive behaviors and anger-hostility items by approximately 33% as reported by child, parent, school, and clinician on 2 standardized scales.

Experts say antidepressant medications may be helpful in treating children with conduct disorder and comorbid major depression.⁸

Recommendations by others

An international consensus statement on ADHD and disruptive behavior disorders (comprising ODD, conduct disorder, and disruptive behavior not otherwise specified) says that psychopharmacologic treatment would not be appropriate for cases of ODD in the absence of psychiatric comorbidity, unless severe aggression or destructive behavior persisted despite attempts at psychosocial interventions of established efficacy.⁴

Evidence summary

No studies specifically evaluate effective treatments for ODD (distinguished by chronic argumentativeness and refusal to comply with adult requests) for adolescent patients. However, there are treatment studies of younger children with ODD and studies of adolescents with the more disruptive behavior problem of conduct disorder (distinguished by a persistent pattern of violating other’s rights, aggression, and illegal acts).

A Clinical Inquiry summarized 8 well-done systematic reviews of ODD treatments of preadolescent children and found improved behavior with parenting interventions and behavioral therapy.¹ Each of the systematic reviews assessed multiple randomized controlled trials (RCTs) using a variety of parenting and behavioral therapy interventions. The most rigorous systematic review (which included 16 RCTs), compared group-based parenting skills training with untreated wait-list controls and found decreased aggression, noncompliance, and temper tantrums by children aged 3 to 10 years (total number of subjects not given) by an average effect size of 0.6 to 2.9. (Effect size is the difference between the means of the experimental and control groups expressed in standard deviations. An effect size of 0.2 is considered small, 0.5 is medium, and 0.8 is moderate to large.) Behavioral therapy (cognitive-behavioral therapy, social problem-solving skills training, parent management training), comprising 12 to 25 sessions with either the child alone or with teachers or parents, decreased disruptive or aggressive behaviors by 20% to 30%.

A 2-year case-control study² of 158 self-referred families with young adolescents (11 to 14 years old) without a formal ODD diagnosis but with reported problem behaviors (defined as smoking, negative engagement in family problem solving, and parental ratings of unpleasant events) found significant improvements (P<.01) with parent-only, teen-only, and parent-teen behavioral interventions for negative engagement behaviors (average of 30% reduction in scores), and with parent and teen interventions for unpleasant events (average of 9% reduction in scores). Interventions comprised 12 weekly 90-minute sessions, with the parent-only group targeting family management practices and communication skills, the teen-only group targeting adolescent self-regulation and pro-social behavior, and the parent-teen group following a structured curriculum.

A meta-analysis³ of 8 RCTs (with a total of 749 children) of various behavioral treatments for conduct disorder and juvenile delinquency among children aged 10 to 17 years found significant reductions in rearrest rates (relative risk [RR]=0.66; 95% confidence interval [CI], 0.44–0.98; number needed to treat [NNT] to prevent 1 rearrest=3.7) and time spent in institutions (mean difference, 51 days) with family and parenting interventions (comprising 1 to 6 months of individual and group parenting training, short and long-term family therapy, and individual and group adolescent interventions).

ODD comorbid with other psychiatric conditions

Approximately half to two-thirds of adolescents with ODD also have ADHD.⁴ A meta-analysis⁵ evaluated 28 studies of stimulant medication (methylphenidate, amphetamine, or pemoline) for children with comorbid ADHD and ODD. A total of 683 patients aged 8 to 18 years were included. Stimulants reduced aggression-related behaviors in these children by an effect size of 0.84 for overt aggression and 0.69 for covert aggression. Stimulants typically reduce aggressive behaviors by similar effect sizes when prescribed for children with ADD alone. The study groups did not separate children with ADHD and ODD from those with ADHD and conduct disorder; they also grouped adolescents together with younger children.

An RCT⁶ of different doses of atomoxetine (Strattera) treatment vs placebo for children ages 8 to 18 (mean age=11) with ADHD alone (N=178) and children with both ADHD and ODD (N=115) found significant effect sizes for atomoxetine in both groups. Two dosages of atomoxetine (1.2 and 1.8 mg/kg/d) produced equivalent effect sizes in the ADHD-only group (0.55 and 0.56); however, the higher dosage had a greater effect size (0.49 vs 0.69) in the group with ODD comorbid with ADHD.

A double-blind crossover RCT⁷ evaluated divalproex (Depakote) vs placebo for 20 children (aged 10 to 18 years) with explosive temper and mood lability who also met DSM-IV criteria for either ODD or conduct disorder. Patients with significant medical problems, such as bipolar disorder, major depression, or mental retardation, were excluded. Divalproex significantly (P=.003) reduced aggressive behaviors and anger-hostility items by approximately 33% as reported by child, parent, school, and clinician on 2 standardized scales.

Experts say antidepressant medications may be helpful in treating children with conduct disorder and comorbid major depression.⁸

Recommendations by others

An international consensus statement on ADHD and disruptive behavior disorders (comprising ODD, conduct disorder, and disruptive behavior not otherwise specified) says that psychopharmacologic treatment would not be appropriate for cases of ODD in the absence of psychiatric comorbidity, unless severe aggression or destructive behavior persisted despite attempts at psychosocial interventions of established efficacy.⁴

Evidence summary

No studies specifically evaluate effective treatments for ODD (distinguished by chronic argumentativeness and refusal to comply with adult requests) for adolescent patients. However, there are treatment studies of younger children with ODD and studies of adolescents with the more disruptive behavior problem of conduct disorder (distinguished by a persistent pattern of violating other’s rights, aggression, and illegal acts).

A Clinical Inquiry summarized 8 well-done systematic reviews of ODD treatments of preadolescent children and found improved behavior with parenting interventions and behavioral therapy.¹ Each of the systematic reviews assessed multiple randomized controlled trials (RCTs) using a variety of parenting and behavioral therapy interventions. The most rigorous systematic review (which included 16 RCTs), compared group-based parenting skills training with untreated wait-list controls and found decreased aggression, noncompliance, and temper tantrums by children aged 3 to 10 years (total number of subjects not given) by an average effect size of 0.6 to 2.9. (Effect size is the difference between the means of the experimental and control groups expressed in standard deviations. An effect size of 0.2 is considered small, 0.5 is medium, and 0.8 is moderate to large.) Behavioral therapy (cognitive-behavioral therapy, social problem-solving skills training, parent management training), comprising 12 to 25 sessions with either the child alone or with teachers or parents, decreased disruptive or aggressive behaviors by 20% to 30%.

A 2-year case-control study² of 158 self-referred families with young adolescents (11 to 14 years old) without a formal ODD diagnosis but with reported problem behaviors (defined as smoking, negative engagement in family problem solving, and parental ratings of unpleasant events) found significant improvements (P<.01) with parent-only, teen-only, and parent-teen behavioral interventions for negative engagement behaviors (average of 30% reduction in scores), and with parent and teen interventions for unpleasant events (average of 9% reduction in scores). Interventions comprised 12 weekly 90-minute sessions, with the parent-only group targeting family management practices and communication skills, the teen-only group targeting adolescent self-regulation and pro-social behavior, and the parent-teen group following a structured curriculum.

A meta-analysis³ of 8 RCTs (with a total of 749 children) of various behavioral treatments for conduct disorder and juvenile delinquency among children aged 10 to 17 years found significant reductions in rearrest rates (relative risk [RR]=0.66; 95% confidence interval [CI], 0.44–0.98; number needed to treat [NNT] to prevent 1 rearrest=3.7) and time spent in institutions (mean difference, 51 days) with family and parenting interventions (comprising 1 to 6 months of individual and group parenting training, short and long-term family therapy, and individual and group adolescent interventions).

ODD comorbid with other psychiatric conditions

Approximately half to two-thirds of adolescents with ODD also have ADHD.⁴ A meta-analysis⁵ evaluated 28 studies of stimulant medication (methylphenidate, amphetamine, or pemoline) for children with comorbid ADHD and ODD. A total of 683 patients aged 8 to 18 years were included. Stimulants reduced aggression-related behaviors in these children by an effect size of 0.84 for overt aggression and 0.69 for covert aggression. Stimulants typically reduce aggressive behaviors by similar effect sizes when prescribed for children with ADD alone. The study groups did not separate children with ADHD and ODD from those with ADHD and conduct disorder; they also grouped adolescents together with younger children.

An RCT⁶ of different doses of atomoxetine (Strattera) treatment vs placebo for children ages 8 to 18 (mean age=11) with ADHD alone (N=178) and children with both ADHD and ODD (N=115) found significant effect sizes for atomoxetine in both groups. Two dosages of atomoxetine (1.2 and 1.8 mg/kg/d) produced equivalent effect sizes in the ADHD-only group (0.55 and 0.56); however, the higher dosage had a greater effect size (0.49 vs 0.69) in the group with ODD comorbid with ADHD.

A double-blind crossover RCT⁷ evaluated divalproex (Depakote) vs placebo for 20 children (aged 10 to 18 years) with explosive temper and mood lability who also met DSM-IV criteria for either ODD or conduct disorder. Patients with significant medical problems, such as bipolar disorder, major depression, or mental retardation, were excluded. Divalproex significantly (P=.003) reduced aggressive behaviors and anger-hostility items by approximately 33% as reported by child, parent, school, and clinician on 2 standardized scales.

Experts say antidepressant medications may be helpful in treating children with conduct disorder and comorbid major depression.⁸

Recommendations by others

An international consensus statement on ADHD and disruptive behavior disorders (comprising ODD, conduct disorder, and disruptive behavior not otherwise specified) says that psychopharmacologic treatment would not be appropriate for cases of ODD in the absence of psychiatric comorbidity, unless severe aggression or destructive behavior persisted despite attempts at psychosocial interventions of established efficacy.⁴

Evidence summary

The TABLE summarizes the recommendations of the US Preventive Services Task Force (USPSTF) with regard to adolescent screening.¹ We identified no additional evidence-based recommendations for screening tests for adolescents.

As shown in the TABLE, rubella susceptibility screening is recommended for all adolescent females (SOR: B). Sexually active adolescent females should routinely be screened for chlamydia, gonorrhea, and cervical cancer. Adolescents at risk of contracting TB, HIV, or syphilis should be screened for those diseases.

Evidence is insufficient to recommend for or against performing the following tests for adolescents: hearing loss screening, anemia screening, clinical or self breast examination, blood pressure screening, screening for overweight, screening for alcohol misuse, screening for depression, and suicide risk screening. For males, evidence is insufficient to recommend for or against: rubella screening, routine rubella vaccination, and chlamydia or gonorrhea screening for sexually active males.

Do not perform the following tests on adolescents because evidence is good that the harms outweigh the benefits: testicular cancer screening using clinical or self-testicular examination, hepatitis B screening, screening for herpes, thyroid cancer screening, screening for scoliosis, and bacteriuria screening in asymptomatic non-pregnant adolescents. Screening for lipid disorders is recommended only for those over age 20 years who have significant risks for coronary artery disease.

TABLE
USPSTF evidence-supported screening tests for adolescents

Recommendations from others

Several professional organizations provide recommendations for adolescent preventive services and screening tests. The American Academy of Family Physicians concurs with the USPSTF recommendations.² The American Academy of Pediatrics (AAP)³ and the American Medical Association⁴ make several recommendations beyond those put forth by the USPSTF, including screening all adolescents for hypertension, risk for hyperlipidemia and adult coronary artery disease, eating disorders/obesity, and tobacco use. They also recommend extending chlamydia and gonorrhea screening to sexually active males.

The AAP also recommends conducting vision and hearing screening, developmental and behavioral assessment, hematocrit or hemoglobin for menstruating adolescents, urine leukocyte esterase for sexually active adolescents, and pelvic exams for sexually active females.

Evidence summary

The TABLE summarizes the recommendations of the US Preventive Services Task Force (USPSTF) with regard to adolescent screening.¹ We identified no additional evidence-based recommendations for screening tests for adolescents.

As shown in the TABLE, rubella susceptibility screening is recommended for all adolescent females (SOR: B). Sexually active adolescent females should routinely be screened for chlamydia, gonorrhea, and cervical cancer. Adolescents at risk of contracting TB, HIV, or syphilis should be screened for those diseases.

Evidence is insufficient to recommend for or against performing the following tests for adolescents: hearing loss screening, anemia screening, clinical or self breast examination, blood pressure screening, screening for overweight, screening for alcohol misuse, screening for depression, and suicide risk screening. For males, evidence is insufficient to recommend for or against: rubella screening, routine rubella vaccination, and chlamydia or gonorrhea screening for sexually active males.

Do not perform the following tests on adolescents because evidence is good that the harms outweigh the benefits: testicular cancer screening using clinical or self-testicular examination, hepatitis B screening, screening for herpes, thyroid cancer screening, screening for scoliosis, and bacteriuria screening in asymptomatic non-pregnant adolescents. Screening for lipid disorders is recommended only for those over age 20 years who have significant risks for coronary artery disease.

TABLE
USPSTF evidence-supported screening tests for adolescents

Recommendations from others

Several professional organizations provide recommendations for adolescent preventive services and screening tests. The American Academy of Family Physicians concurs with the USPSTF recommendations.² The American Academy of Pediatrics (AAP)³ and the American Medical Association⁴ make several recommendations beyond those put forth by the USPSTF, including screening all adolescents for hypertension, risk for hyperlipidemia and adult coronary artery disease, eating disorders/obesity, and tobacco use. They also recommend extending chlamydia and gonorrhea screening to sexually active males.

The AAP also recommends conducting vision and hearing screening, developmental and behavioral assessment, hematocrit or hemoglobin for menstruating adolescents, urine leukocyte esterase for sexually active adolescents, and pelvic exams for sexually active females.

Evidence summary

The TABLE summarizes the recommendations of the US Preventive Services Task Force (USPSTF) with regard to adolescent screening.¹ We identified no additional evidence-based recommendations for screening tests for adolescents.

As shown in the TABLE, rubella susceptibility screening is recommended for all adolescent females (SOR: B). Sexually active adolescent females should routinely be screened for chlamydia, gonorrhea, and cervical cancer. Adolescents at risk of contracting TB, HIV, or syphilis should be screened for those diseases.

Evidence is insufficient to recommend for or against performing the following tests for adolescents: hearing loss screening, anemia screening, clinical or self breast examination, blood pressure screening, screening for overweight, screening for alcohol misuse, screening for depression, and suicide risk screening. For males, evidence is insufficient to recommend for or against: rubella screening, routine rubella vaccination, and chlamydia or gonorrhea screening for sexually active males.

Do not perform the following tests on adolescents because evidence is good that the harms outweigh the benefits: testicular cancer screening using clinical or self-testicular examination, hepatitis B screening, screening for herpes, thyroid cancer screening, screening for scoliosis, and bacteriuria screening in asymptomatic non-pregnant adolescents. Screening for lipid disorders is recommended only for those over age 20 years who have significant risks for coronary artery disease.

TABLE
USPSTF evidence-supported screening tests for adolescents

Recommendations from others

Several professional organizations provide recommendations for adolescent preventive services and screening tests. The American Academy of Family Physicians concurs with the USPSTF recommendations.² The American Academy of Pediatrics (AAP)³ and the American Medical Association⁴ make several recommendations beyond those put forth by the USPSTF, including screening all adolescents for hypertension, risk for hyperlipidemia and adult coronary artery disease, eating disorders/obesity, and tobacco use. They also recommend extending chlamydia and gonorrhea screening to sexually active males.

The AAP also recommends conducting vision and hearing screening, developmental and behavioral assessment, hematocrit or hemoglobin for menstruating adolescents, urine leukocyte esterase for sexually active adolescents, and pelvic exams for sexually active females.

Evidence summary

A prospective study¹ evaluated 5 patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) who took 20 mg of pravastatin daily for 6 months. Liver enzyme levels at baseline were no more than 3 times the upper limit of normal. All 5 patients had normalized liver enzymes at the end of the study.

A 6-month unblinded study² found similar results among 44 adult patients with biopsy-confirmed NASH. Twenty-seven hyperlipidemic patients (aged 50±1.4 years) with an average alanine aminotransferase (ALT) of 81.8 U/L took 10 mg of atorvastatin daily. Seventeen normolipidemic patients (aged 43.7±1.8 years) with an average ALT of 76.0 U/L took ursodeoxycholic acid (UDCA) 13–15 mg/kg/d for the same duration; 59% of atorvastatin-treated patients normalized liver enzyme levels compared with 23% in the UDCA group. On computed tomography scanning, both groups showed improvement in liver densities, suggesting improvement of fatty liver.²

Another study³ included patients with biopsy-confirmed fatty liver and elevated ALT levels greater than 1.5 times the upper limit of normal. In this 24-week study, 23 predominantly hypertriglyceridemic patients took omega-3 fatty acids, 5 mL 3 times daily, 28 hypercholesterolemic patients took atorvastatin 20 mg daily, and 21 dyslipidemic patients with a body mass index >27.0 took orlistat 120 mg 3 times daily. ALT levels decreased in all 3 groups during the study. Ultrasonography showed normal liver echo pattern at the end of treatment for 35% of omega-3 patients, 61% of atorvastatin patients, and 86% of orlistat patients. No serious adverse events were observed.

Two retrospective studies of patients with baseline elevated transaminases who took statins showed no significant increase in transaminase levels during treatment compared with patients with elevated transaminases who did not take statins. One study⁴ reviewed electronic medical records for patients with preexisting elevated liver enzymes who initiated statin therapy (atorvastatin, simvastatin, or fluvastatin) and had follow-up labs drawn 6 months later (cohort 1, n=342). The comparison groups included patients with normal liver enzymes who initiated statins (cohort 2, n=1437) and patients with elevated baseline liver enzymes who did not take statins (cohort 3, n=2245). At follow-up, 4.7% of cohort 1 patients had mild-to-moderate elevations in liver enzymes, which did not differ significantly (P=.2) from those in cohort 3. Within cohort 2, 1.9% experienced mild-to-moderate elevations of transaminases (defined as less than 10 times the upper limit of normal).

Another retrospective cohort study⁵ of patients with preexisting elevated liver enzymes found comparable results with lovastatin. Among lovastatin patients (n=135), 6.6% had mild-to-moderate elevations in transaminases during therapy vs 11% of the cohort of patients with preexisting elevated liver enzymes who did not take statins. This difference was not statistically significant (P=.2).

Recommendations from others

The National Cholesterol Education Project⁶ states that “the incidence of clinically important transaminase elevations in the large statin trials is the same for statins as for placebo. Progression to liver failure is exceedingly rare, if it occurs.” They further state that the use of statins for persons with decompensated liver disease or advanced cirrhosis depends on clinical judgment, but that their use in NASH is considered safe.

The FDA states that statins are contraindicated in cholestasis and active liver disease, and that statins should be discontinued when liver enzymes increase to 3 times the upper limits of normal.

Evidence summary

A prospective study¹ evaluated 5 patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) who took 20 mg of pravastatin daily for 6 months. Liver enzyme levels at baseline were no more than 3 times the upper limit of normal. All 5 patients had normalized liver enzymes at the end of the study.

A 6-month unblinded study² found similar results among 44 adult patients with biopsy-confirmed NASH. Twenty-seven hyperlipidemic patients (aged 50±1.4 years) with an average alanine aminotransferase (ALT) of 81.8 U/L took 10 mg of atorvastatin daily. Seventeen normolipidemic patients (aged 43.7±1.8 years) with an average ALT of 76.0 U/L took ursodeoxycholic acid (UDCA) 13–15 mg/kg/d for the same duration; 59% of atorvastatin-treated patients normalized liver enzyme levels compared with 23% in the UDCA group. On computed tomography scanning, both groups showed improvement in liver densities, suggesting improvement of fatty liver.²

Another study³ included patients with biopsy-confirmed fatty liver and elevated ALT levels greater than 1.5 times the upper limit of normal. In this 24-week study, 23 predominantly hypertriglyceridemic patients took omega-3 fatty acids, 5 mL 3 times daily, 28 hypercholesterolemic patients took atorvastatin 20 mg daily, and 21 dyslipidemic patients with a body mass index >27.0 took orlistat 120 mg 3 times daily. ALT levels decreased in all 3 groups during the study. Ultrasonography showed normal liver echo pattern at the end of treatment for 35% of omega-3 patients, 61% of atorvastatin patients, and 86% of orlistat patients. No serious adverse events were observed.

Two retrospective studies of patients with baseline elevated transaminases who took statins showed no significant increase in transaminase levels during treatment compared with patients with elevated transaminases who did not take statins. One study⁴ reviewed electronic medical records for patients with preexisting elevated liver enzymes who initiated statin therapy (atorvastatin, simvastatin, or fluvastatin) and had follow-up labs drawn 6 months later (cohort 1, n=342). The comparison groups included patients with normal liver enzymes who initiated statins (cohort 2, n=1437) and patients with elevated baseline liver enzymes who did not take statins (cohort 3, n=2245). At follow-up, 4.7% of cohort 1 patients had mild-to-moderate elevations in liver enzymes, which did not differ significantly (P=.2) from those in cohort 3. Within cohort 2, 1.9% experienced mild-to-moderate elevations of transaminases (defined as less than 10 times the upper limit of normal).

Another retrospective cohort study⁵ of patients with preexisting elevated liver enzymes found comparable results with lovastatin. Among lovastatin patients (n=135), 6.6% had mild-to-moderate elevations in transaminases during therapy vs 11% of the cohort of patients with preexisting elevated liver enzymes who did not take statins. This difference was not statistically significant (P=.2).

Recommendations from others

The National Cholesterol Education Project⁶ states that “the incidence of clinically important transaminase elevations in the large statin trials is the same for statins as for placebo. Progression to liver failure is exceedingly rare, if it occurs.” They further state that the use of statins for persons with decompensated liver disease or advanced cirrhosis depends on clinical judgment, but that their use in NASH is considered safe.

The FDA states that statins are contraindicated in cholestasis and active liver disease, and that statins should be discontinued when liver enzymes increase to 3 times the upper limits of normal.

Evidence summary

A prospective study¹ evaluated 5 patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) who took 20 mg of pravastatin daily for 6 months. Liver enzyme levels at baseline were no more than 3 times the upper limit of normal. All 5 patients had normalized liver enzymes at the end of the study.

A 6-month unblinded study² found similar results among 44 adult patients with biopsy-confirmed NASH. Twenty-seven hyperlipidemic patients (aged 50±1.4 years) with an average alanine aminotransferase (ALT) of 81.8 U/L took 10 mg of atorvastatin daily. Seventeen normolipidemic patients (aged 43.7±1.8 years) with an average ALT of 76.0 U/L took ursodeoxycholic acid (UDCA) 13–15 mg/kg/d for the same duration; 59% of atorvastatin-treated patients normalized liver enzyme levels compared with 23% in the UDCA group. On computed tomography scanning, both groups showed improvement in liver densities, suggesting improvement of fatty liver.²

Another study³ included patients with biopsy-confirmed fatty liver and elevated ALT levels greater than 1.5 times the upper limit of normal. In this 24-week study, 23 predominantly hypertriglyceridemic patients took omega-3 fatty acids, 5 mL 3 times daily, 28 hypercholesterolemic patients took atorvastatin 20 mg daily, and 21 dyslipidemic patients with a body mass index >27.0 took orlistat 120 mg 3 times daily. ALT levels decreased in all 3 groups during the study. Ultrasonography showed normal liver echo pattern at the end of treatment for 35% of omega-3 patients, 61% of atorvastatin patients, and 86% of orlistat patients. No serious adverse events were observed.

Two retrospective studies of patients with baseline elevated transaminases who took statins showed no significant increase in transaminase levels during treatment compared with patients with elevated transaminases who did not take statins. One study⁴ reviewed electronic medical records for patients with preexisting elevated liver enzymes who initiated statin therapy (atorvastatin, simvastatin, or fluvastatin) and had follow-up labs drawn 6 months later (cohort 1, n=342). The comparison groups included patients with normal liver enzymes who initiated statins (cohort 2, n=1437) and patients with elevated baseline liver enzymes who did not take statins (cohort 3, n=2245). At follow-up, 4.7% of cohort 1 patients had mild-to-moderate elevations in liver enzymes, which did not differ significantly (P=.2) from those in cohort 3. Within cohort 2, 1.9% experienced mild-to-moderate elevations of transaminases (defined as less than 10 times the upper limit of normal).

Another retrospective cohort study⁵ of patients with preexisting elevated liver enzymes found comparable results with lovastatin. Among lovastatin patients (n=135), 6.6% had mild-to-moderate elevations in transaminases during therapy vs 11% of the cohort of patients with preexisting elevated liver enzymes who did not take statins. This difference was not statistically significant (P=.2).

Recommendations from others

The National Cholesterol Education Project⁶ states that “the incidence of clinically important transaminase elevations in the large statin trials is the same for statins as for placebo. Progression to liver failure is exceedingly rare, if it occurs.” They further state that the use of statins for persons with decompensated liver disease or advanced cirrhosis depends on clinical judgment, but that their use in NASH is considered safe.

The FDA states that statins are contraindicated in cholestasis and active liver disease, and that statins should be discontinued when liver enzymes increase to 3 times the upper limits of normal.

Evidence summary

A prospective cohort study¹ evaluated dobutamine or dipyridamole pharmacologic stress echocardiography among 904 primary care patients with either typical or atypical chest pain. Patients were enrolled into the study if they had normal resting wall motion, sinus rhythm, and had no history of coronary artery disease, unstable angina, or PTCA. Patients (average age 61 years, 42% men) were followed for an average of 44 months for primary cardiovascular endpoints (fatal or nonfatal myocardial infarction [MI], unstable angina, PTCA, or cardiac death). A negative or positive stress echocardiography is defined as the absence or presence of abnormal cardiac wall motion on either exercise or pharmacologic stress echocardiography. Eighteen percent of patients had a positive pharmacologic stress echocardiography. Over the length of the study, 81 of 904 patients (9%) suffered a cardiovascular event. Patients with a negative pharmacologic stress echocardiography had a mean annual probability of a cardiovascular event of 0.8% vs 8.5% with a positive pharmacologic stress echocardiography (P<0001). The 4-year infarct-free negative predictive value (NPV) of pharmacologic stress echocardiography was 97%, and the positive predictive value (PPV) was 70%.

A similar prospective cohort study² evaluated 105 patients (50% men) with atypical chest pain in an emergency department setting with either exercise or dobutamine/atropine stress echocardiography. The average patient age was 55 years and follow-up was 2.8 years. Patients were clinically stable, had normal or nondiagnostic electrocardiogram (ECG), normal cardiac enzymes, normal left ventricular function, and no history of coronary artery disease or unstable angina. Cardiovascular endpoints included fatal or nonfatal MI, unstable angina, PTCA, or cardiac death. A total of 7 patients (7%) suffered a cardiovascular event during the follow-up period. Positive stress echocardiography results occurred for 9% of patients. The NPV was 99% and the PPV was 75%.

Three other cohort studies^3-5 evaluated exercise or dobutamine/atropine stress echocardiography for a total of 615 patients (48%–67% men, average age 56–58 years) presenting to an emergency department with classical cardiac or atypical chest pain. Patients had normal or nondiagnostic ECG, negative cardiac enzymes, and either no history of coronary artery disease^3,4 or known coronary artery disease of unknown significance.⁵ A positive stress echocardiography was obtained for 4.8% to 42% of patients in the cohorts. During 6 months of follow-up, cardiovascular events occurred in 4 of 145 patients (3%),³ 22 of 227 patients (6%),⁴ and in 11 of 80 patients (14%).⁵ At 6-month follow-up, exercise stress echocardiography had a NPV of 99.3% and a PPV of 43%.³ Dobutamine/atropine stress echocardiography had a NPV of 95% to 96% and a PPV of 25% to 31%.^4,5

One retrospective review⁶ evaluated exercise and dobutamine/atropine stress echocardiography and stress ECG for 661 low-risk outpatients (48% men, average age 58 years) with atypical chest pain. All patients had normal left ventricular function and no history of coronary artery disease and were followed for an average of 23 months. A positive stress echocardiography test occurred among 16% of the patient population.

During follow-up, 41 of 661 patients (6%) suffered a cardiovascular event. For either exercise or dobutamine/atropine stress echocardiography, the NPV was 99% at 12 months and 96% at 30 months. Patients with a positive stress echocardiography test and a negative stress ECG had a 66% event-free survival rate. Event-free survival rate for patients with a negative stress echocardiography and a positive or negative stress ECG was 97% and 96%, respectively.

Recommendations from others

The American College of Cardiology⁷ gives a Class I recommendation (tests for which there is evidence or general agreement that a given procedure or treatment is useful and effective) for standard echocardiogram for evaluation of chest pain for patients with suspected acute myocardial ischemia (when baseline ECG and other laboratory markers are nondiagnostic and when the study can be obtained during pain or within minutes after its abatement).

It gives a Class IIa recommendation (tests for which there is conflicting evidence or divergence of opinion, but favoring usefulness) to stress echocardiography for the detection of myocardial ischemia for women with an intermediate pretest likelihood of coronary artery disease. It also gives a Class IIa recommendation to stress echocardiography for determining the prognosis of myocardial ischemia among patients for whom ECG assessment is less reliable. This group comprises patients with the following ECG abnormalities: pre-excitation syndrome (such as Wolff-Parkinson-White), electronically paced ventricular rhythm, more than 1 mm of ST depression at rest, and complete left bundle branch block.

Evidence summary

A prospective cohort study¹ evaluated dobutamine or dipyridamole pharmacologic stress echocardiography among 904 primary care patients with either typical or atypical chest pain. Patients were enrolled into the study if they had normal resting wall motion, sinus rhythm, and had no history of coronary artery disease, unstable angina, or PTCA. Patients (average age 61 years, 42% men) were followed for an average of 44 months for primary cardiovascular endpoints (fatal or nonfatal myocardial infarction [MI], unstable angina, PTCA, or cardiac death). A negative or positive stress echocardiography is defined as the absence or presence of abnormal cardiac wall motion on either exercise or pharmacologic stress echocardiography. Eighteen percent of patients had a positive pharmacologic stress echocardiography. Over the length of the study, 81 of 904 patients (9%) suffered a cardiovascular event. Patients with a negative pharmacologic stress echocardiography had a mean annual probability of a cardiovascular event of 0.8% vs 8.5% with a positive pharmacologic stress echocardiography (P<0001). The 4-year infarct-free negative predictive value (NPV) of pharmacologic stress echocardiography was 97%, and the positive predictive value (PPV) was 70%.

A similar prospective cohort study² evaluated 105 patients (50% men) with atypical chest pain in an emergency department setting with either exercise or dobutamine/atropine stress echocardiography. The average patient age was 55 years and follow-up was 2.8 years. Patients were clinically stable, had normal or nondiagnostic electrocardiogram (ECG), normal cardiac enzymes, normal left ventricular function, and no history of coronary artery disease or unstable angina. Cardiovascular endpoints included fatal or nonfatal MI, unstable angina, PTCA, or cardiac death. A total of 7 patients (7%) suffered a cardiovascular event during the follow-up period. Positive stress echocardiography results occurred for 9% of patients. The NPV was 99% and the PPV was 75%.

Three other cohort studies^3-5 evaluated exercise or dobutamine/atropine stress echocardiography for a total of 615 patients (48%–67% men, average age 56–58 years) presenting to an emergency department with classical cardiac or atypical chest pain. Patients had normal or nondiagnostic ECG, negative cardiac enzymes, and either no history of coronary artery disease^3,4 or known coronary artery disease of unknown significance.⁵ A positive stress echocardiography was obtained for 4.8% to 42% of patients in the cohorts. During 6 months of follow-up, cardiovascular events occurred in 4 of 145 patients (3%),³ 22 of 227 patients (6%),⁴ and in 11 of 80 patients (14%).⁵ At 6-month follow-up, exercise stress echocardiography had a NPV of 99.3% and a PPV of 43%.³ Dobutamine/atropine stress echocardiography had a NPV of 95% to 96% and a PPV of 25% to 31%.^4,5

One retrospective review⁶ evaluated exercise and dobutamine/atropine stress echocardiography and stress ECG for 661 low-risk outpatients (48% men, average age 58 years) with atypical chest pain. All patients had normal left ventricular function and no history of coronary artery disease and were followed for an average of 23 months. A positive stress echocardiography test occurred among 16% of the patient population.

During follow-up, 41 of 661 patients (6%) suffered a cardiovascular event. For either exercise or dobutamine/atropine stress echocardiography, the NPV was 99% at 12 months and 96% at 30 months. Patients with a positive stress echocardiography test and a negative stress ECG had a 66% event-free survival rate. Event-free survival rate for patients with a negative stress echocardiography and a positive or negative stress ECG was 97% and 96%, respectively.

Recommendations from others

The American College of Cardiology⁷ gives a Class I recommendation (tests for which there is evidence or general agreement that a given procedure or treatment is useful and effective) for standard echocardiogram for evaluation of chest pain for patients with suspected acute myocardial ischemia (when baseline ECG and other laboratory markers are nondiagnostic and when the study can be obtained during pain or within minutes after its abatement).

It gives a Class IIa recommendation (tests for which there is conflicting evidence or divergence of opinion, but favoring usefulness) to stress echocardiography for the detection of myocardial ischemia for women with an intermediate pretest likelihood of coronary artery disease. It also gives a Class IIa recommendation to stress echocardiography for determining the prognosis of myocardial ischemia among patients for whom ECG assessment is less reliable. This group comprises patients with the following ECG abnormalities: pre-excitation syndrome (such as Wolff-Parkinson-White), electronically paced ventricular rhythm, more than 1 mm of ST depression at rest, and complete left bundle branch block.

Evidence summary

A prospective cohort study¹ evaluated dobutamine or dipyridamole pharmacologic stress echocardiography among 904 primary care patients with either typical or atypical chest pain. Patients were enrolled into the study if they had normal resting wall motion, sinus rhythm, and had no history of coronary artery disease, unstable angina, or PTCA. Patients (average age 61 years, 42% men) were followed for an average of 44 months for primary cardiovascular endpoints (fatal or nonfatal myocardial infarction [MI], unstable angina, PTCA, or cardiac death). A negative or positive stress echocardiography is defined as the absence or presence of abnormal cardiac wall motion on either exercise or pharmacologic stress echocardiography. Eighteen percent of patients had a positive pharmacologic stress echocardiography. Over the length of the study, 81 of 904 patients (9%) suffered a cardiovascular event. Patients with a negative pharmacologic stress echocardiography had a mean annual probability of a cardiovascular event of 0.8% vs 8.5% with a positive pharmacologic stress echocardiography (P<0001). The 4-year infarct-free negative predictive value (NPV) of pharmacologic stress echocardiography was 97%, and the positive predictive value (PPV) was 70%.

A similar prospective cohort study² evaluated 105 patients (50% men) with atypical chest pain in an emergency department setting with either exercise or dobutamine/atropine stress echocardiography. The average patient age was 55 years and follow-up was 2.8 years. Patients were clinically stable, had normal or nondiagnostic electrocardiogram (ECG), normal cardiac enzymes, normal left ventricular function, and no history of coronary artery disease or unstable angina. Cardiovascular endpoints included fatal or nonfatal MI, unstable angina, PTCA, or cardiac death. A total of 7 patients (7%) suffered a cardiovascular event during the follow-up period. Positive stress echocardiography results occurred for 9% of patients. The NPV was 99% and the PPV was 75%.

Three other cohort studies^3-5 evaluated exercise or dobutamine/atropine stress echocardiography for a total of 615 patients (48%–67% men, average age 56–58 years) presenting to an emergency department with classical cardiac or atypical chest pain. Patients had normal or nondiagnostic ECG, negative cardiac enzymes, and either no history of coronary artery disease^3,4 or known coronary artery disease of unknown significance.⁵ A positive stress echocardiography was obtained for 4.8% to 42% of patients in the cohorts. During 6 months of follow-up, cardiovascular events occurred in 4 of 145 patients (3%),³ 22 of 227 patients (6%),⁴ and in 11 of 80 patients (14%).⁵ At 6-month follow-up, exercise stress echocardiography had a NPV of 99.3% and a PPV of 43%.³ Dobutamine/atropine stress echocardiography had a NPV of 95% to 96% and a PPV of 25% to 31%.^4,5

One retrospective review⁶ evaluated exercise and dobutamine/atropine stress echocardiography and stress ECG for 661 low-risk outpatients (48% men, average age 58 years) with atypical chest pain. All patients had normal left ventricular function and no history of coronary artery disease and were followed for an average of 23 months. A positive stress echocardiography test occurred among 16% of the patient population.

During follow-up, 41 of 661 patients (6%) suffered a cardiovascular event. For either exercise or dobutamine/atropine stress echocardiography, the NPV was 99% at 12 months and 96% at 30 months. Patients with a positive stress echocardiography test and a negative stress ECG had a 66% event-free survival rate. Event-free survival rate for patients with a negative stress echocardiography and a positive or negative stress ECG was 97% and 96%, respectively.

Recommendations from others

The American College of Cardiology⁷ gives a Class I recommendation (tests for which there is evidence or general agreement that a given procedure or treatment is useful and effective) for standard echocardiogram for evaluation of chest pain for patients with suspected acute myocardial ischemia (when baseline ECG and other laboratory markers are nondiagnostic and when the study can be obtained during pain or within minutes after its abatement).

It gives a Class IIa recommendation (tests for which there is conflicting evidence or divergence of opinion, but favoring usefulness) to stress echocardiography for the detection of myocardial ischemia for women with an intermediate pretest likelihood of coronary artery disease. It also gives a Class IIa recommendation to stress echocardiography for determining the prognosis of myocardial ischemia among patients for whom ECG assessment is less reliable. This group comprises patients with the following ECG abnormalities: pre-excitation syndrome (such as Wolff-Parkinson-White), electronically paced ventricular rhythm, more than 1 mm of ST depression at rest, and complete left bundle branch block.

Evidence summary

A 2002 Agency for Healthcare Research and Quality systematic review on the diagnosis and treatment of allergic rhinitis found no RCTs comparing antihistamines or nasal corticosteroids with immunotherapy.² Our literature review found 4 studies not included in this report that compared immunotherapy with nasal steroids or oral antihistamines.^3-6 Only 2 of these examined patient-oriented outcomes and both are of poor quality.^3,6 One study reported that inhaled nasal steroid therapy was superior to a nonstandard immunotherapy for ragweed pollen–induced rhinitis.³ The second study allowed patients to choose a treatment arm; it found that immunotherapy was superior to treatment with antihistamines and nasal steroids for patients who chose it.⁶

For patients requiring medication, studies comparing antihistamines with nasal corticosteroids have documented the superiority of intranasal steroids for symptom control of allergic rhinitis.^2,7

The effectiveness of immunotherapy has been documented in more than 40 placebo-controlled trials. However, the patients involved in these trials were often concurrently treated with allergy medications.⁸ In standard practice, immunotherapy is not recommended for most patients with seasonal allergic rhinitis unless avoidance measures and symptomatic therapy are ineffective, have adverse effects, or are not feasible.⁹ Studies indicate that immunotherapy is effective for several years after treatment is discontinued.¹⁰

A review of recent placebo-controlled trials indicates that the risk of developing asthma among patients with allergic rhinoconjunctivitis is significantly reduced when patients receive specific immunotherapy.¹¹ However, allergy immunotherapy presents risk of systemic reactions, with one study reporting a 0.5% risk of systemic reactions per year of therapy.¹²

Recommendations from others

The American College of Allergy, Asthma, and Immunology recommends that effective management of allergic rhinitis may require combinations of medications—antihistamines, decongestants, nasal corticosteroids, and anticholinergic agents as well as aggressive avoidance of rhinitis triggers. Consider allergen immunotherapy in carefully selected patients in consultation with an allergist-immunologist.¹⁰

Evidence summary

A 2002 Agency for Healthcare Research and Quality systematic review on the diagnosis and treatment of allergic rhinitis found no RCTs comparing antihistamines or nasal corticosteroids with immunotherapy.² Our literature review found 4 studies not included in this report that compared immunotherapy with nasal steroids or oral antihistamines.^3-6 Only 2 of these examined patient-oriented outcomes and both are of poor quality.^3,6 One study reported that inhaled nasal steroid therapy was superior to a nonstandard immunotherapy for ragweed pollen–induced rhinitis.³ The second study allowed patients to choose a treatment arm; it found that immunotherapy was superior to treatment with antihistamines and nasal steroids for patients who chose it.⁶

For patients requiring medication, studies comparing antihistamines with nasal corticosteroids have documented the superiority of intranasal steroids for symptom control of allergic rhinitis.^2,7

The effectiveness of immunotherapy has been documented in more than 40 placebo-controlled trials. However, the patients involved in these trials were often concurrently treated with allergy medications.⁸ In standard practice, immunotherapy is not recommended for most patients with seasonal allergic rhinitis unless avoidance measures and symptomatic therapy are ineffective, have adverse effects, or are not feasible.⁹ Studies indicate that immunotherapy is effective for several years after treatment is discontinued.¹⁰

A review of recent placebo-controlled trials indicates that the risk of developing asthma among patients with allergic rhinoconjunctivitis is significantly reduced when patients receive specific immunotherapy.¹¹ However, allergy immunotherapy presents risk of systemic reactions, with one study reporting a 0.5% risk of systemic reactions per year of therapy.¹²

Recommendations from others

The American College of Allergy, Asthma, and Immunology recommends that effective management of allergic rhinitis may require combinations of medications—antihistamines, decongestants, nasal corticosteroids, and anticholinergic agents as well as aggressive avoidance of rhinitis triggers. Consider allergen immunotherapy in carefully selected patients in consultation with an allergist-immunologist.¹⁰

Evidence summary

A 2002 Agency for Healthcare Research and Quality systematic review on the diagnosis and treatment of allergic rhinitis found no RCTs comparing antihistamines or nasal corticosteroids with immunotherapy.² Our literature review found 4 studies not included in this report that compared immunotherapy with nasal steroids or oral antihistamines.^3-6 Only 2 of these examined patient-oriented outcomes and both are of poor quality.^3,6 One study reported that inhaled nasal steroid therapy was superior to a nonstandard immunotherapy for ragweed pollen–induced rhinitis.³ The second study allowed patients to choose a treatment arm; it found that immunotherapy was superior to treatment with antihistamines and nasal steroids for patients who chose it.⁶

For patients requiring medication, studies comparing antihistamines with nasal corticosteroids have documented the superiority of intranasal steroids for symptom control of allergic rhinitis.^2,7

The effectiveness of immunotherapy has been documented in more than 40 placebo-controlled trials. However, the patients involved in these trials were often concurrently treated with allergy medications.⁸ In standard practice, immunotherapy is not recommended for most patients with seasonal allergic rhinitis unless avoidance measures and symptomatic therapy are ineffective, have adverse effects, or are not feasible.⁹ Studies indicate that immunotherapy is effective for several years after treatment is discontinued.¹⁰

A review of recent placebo-controlled trials indicates that the risk of developing asthma among patients with allergic rhinoconjunctivitis is significantly reduced when patients receive specific immunotherapy.¹¹ However, allergy immunotherapy presents risk of systemic reactions, with one study reporting a 0.5% risk of systemic reactions per year of therapy.¹²

Recommendations from others

The American College of Allergy, Asthma, and Immunology recommends that effective management of allergic rhinitis may require combinations of medications—antihistamines, decongestants, nasal corticosteroids, and anticholinergic agents as well as aggressive avoidance of rhinitis triggers. Consider allergen immunotherapy in carefully selected patients in consultation with an allergist-immunologist.¹⁰

Evidence summary

Two different assays are commonly available for urine drug testing. The immunoassay is quick, highly sensitive, and relatively inexpensive but may lack specificity. It tests for classes of drugs (such as opiates) without distinguishing among individual drugs within that class. Gas chromatography in combination with mass spectrometry (GC-MS) is a more expensive and time-consuming test, but is the gold standard for confirming a positive result on immunoassay. By definition, all positive results on GC-MS are true positives.

Reports of false-positive urine drug screening for substances of abuse are infrequent and limited to case reports and a few controlled-exposure studies. The TABLE lists some of the substances reported to cause false-positive results.

Positive confirmation tests may occur in urine specimens from patients who legally or unknowingly ingest products that contain drugs of abuse. In these instances, the finding is a true positive but may not reflect drug abuse by the client. Many products available without prescription outside of the US contain opiates (eg, Donnagel PG from Canada).¹ Several controlled-exposure studies have shown that as little as 1 poppy seed muffin (about 15 g of seed) can produce detectable amounts of morphine and codeine by immunoassay as well as GC-MS.^1,2 In 1998, the federal government increased the threshold defining a positive screen for urine morphine and codeine from 300 to 2000 ng/mL to reduce spurious reports of opiate-positive tests from poppy seed consumption.^1,2

Substances that do not produce positive urine drug screens include passively inhaled crack cocaine or marijuana (unless “extreme”), and ingested products containing hemp or other common herbal preparations.^1,2,10 In one study, 6 volunteers in an 8×8×7-ft enclosed room were exposed to 200 mg freebase cocaine vapor; none of their urine samples exceeded the federal GC-MS threshold. In a similar study of 3 non-smokers exposed to 8 marijuana smokers (smoking 32 joints) in a 10×10×8-ft enclosed room, no samples from the nonsmokers exceeded the federal GC-MS threshold.² In an exposure study of 90 volunteers who ingested 8 different herbal preparations, there were no positive urine drug screens.¹

TABLE
Substances reported to cause false-positive urine drug screen results

Recommendations from others

The US Department of Health and Human Services requires confirmation of positive immunoassay results by GC-MS for drug testing in the workplace.¹ The College of American Pathologists, the principal organization of board-certified pathologists, states: “Confirmation testing, a standard of practice in forensic toxicology, should be performed in clinical toxicology whenever possible.”¹¹

Evidence summary

Two different assays are commonly available for urine drug testing. The immunoassay is quick, highly sensitive, and relatively inexpensive but may lack specificity. It tests for classes of drugs (such as opiates) without distinguishing among individual drugs within that class. Gas chromatography in combination with mass spectrometry (GC-MS) is a more expensive and time-consuming test, but is the gold standard for confirming a positive result on immunoassay. By definition, all positive results on GC-MS are true positives.

Reports of false-positive urine drug screening for substances of abuse are infrequent and limited to case reports and a few controlled-exposure studies. The TABLE lists some of the substances reported to cause false-positive results.

Positive confirmation tests may occur in urine specimens from patients who legally or unknowingly ingest products that contain drugs of abuse. In these instances, the finding is a true positive but may not reflect drug abuse by the client. Many products available without prescription outside of the US contain opiates (eg, Donnagel PG from Canada).¹ Several controlled-exposure studies have shown that as little as 1 poppy seed muffin (about 15 g of seed) can produce detectable amounts of morphine and codeine by immunoassay as well as GC-MS.^1,2 In 1998, the federal government increased the threshold defining a positive screen for urine morphine and codeine from 300 to 2000 ng/mL to reduce spurious reports of opiate-positive tests from poppy seed consumption.^1,2

Substances that do not produce positive urine drug screens include passively inhaled crack cocaine or marijuana (unless “extreme”), and ingested products containing hemp or other common herbal preparations.^1,2,10 In one study, 6 volunteers in an 8×8×7-ft enclosed room were exposed to 200 mg freebase cocaine vapor; none of their urine samples exceeded the federal GC-MS threshold. In a similar study of 3 non-smokers exposed to 8 marijuana smokers (smoking 32 joints) in a 10×10×8-ft enclosed room, no samples from the nonsmokers exceeded the federal GC-MS threshold.² In an exposure study of 90 volunteers who ingested 8 different herbal preparations, there were no positive urine drug screens.¹

TABLE
Substances reported to cause false-positive urine drug screen results

Recommendations from others

The US Department of Health and Human Services requires confirmation of positive immunoassay results by GC-MS for drug testing in the workplace.¹ The College of American Pathologists, the principal organization of board-certified pathologists, states: “Confirmation testing, a standard of practice in forensic toxicology, should be performed in clinical toxicology whenever possible.”¹¹

Evidence summary

Two different assays are commonly available for urine drug testing. The immunoassay is quick, highly sensitive, and relatively inexpensive but may lack specificity. It tests for classes of drugs (such as opiates) without distinguishing among individual drugs within that class. Gas chromatography in combination with mass spectrometry (GC-MS) is a more expensive and time-consuming test, but is the gold standard for confirming a positive result on immunoassay. By definition, all positive results on GC-MS are true positives.

Reports of false-positive urine drug screening for substances of abuse are infrequent and limited to case reports and a few controlled-exposure studies. The TABLE lists some of the substances reported to cause false-positive results.

Positive confirmation tests may occur in urine specimens from patients who legally or unknowingly ingest products that contain drugs of abuse. In these instances, the finding is a true positive but may not reflect drug abuse by the client. Many products available without prescription outside of the US contain opiates (eg, Donnagel PG from Canada).¹ Several controlled-exposure studies have shown that as little as 1 poppy seed muffin (about 15 g of seed) can produce detectable amounts of morphine and codeine by immunoassay as well as GC-MS.^1,2 In 1998, the federal government increased the threshold defining a positive screen for urine morphine and codeine from 300 to 2000 ng/mL to reduce spurious reports of opiate-positive tests from poppy seed consumption.^1,2

Substances that do not produce positive urine drug screens include passively inhaled crack cocaine or marijuana (unless “extreme”), and ingested products containing hemp or other common herbal preparations.^1,2,10 In one study, 6 volunteers in an 8×8×7-ft enclosed room were exposed to 200 mg freebase cocaine vapor; none of their urine samples exceeded the federal GC-MS threshold. In a similar study of 3 non-smokers exposed to 8 marijuana smokers (smoking 32 joints) in a 10×10×8-ft enclosed room, no samples from the nonsmokers exceeded the federal GC-MS threshold.² In an exposure study of 90 volunteers who ingested 8 different herbal preparations, there were no positive urine drug screens.¹

TABLE
Substances reported to cause false-positive urine drug screen results

Recommendations from others

The US Department of Health and Human Services requires confirmation of positive immunoassay results by GC-MS for drug testing in the workplace.¹ The College of American Pathologists, the principal organization of board-certified pathologists, states: “Confirmation testing, a standard of practice in forensic toxicology, should be performed in clinical toxicology whenever possible.”¹¹