Laura Leach, MLIS

Evidence summary

Studies evaluating whether menopausal women experience fatigue at higher rates than pre-or perimenopausal women are of variable quality and yield conflicting results.¹ Though several studies suggest an association between fatigue among menopausal women and disease states, poor methodology limits the strength of their findings.

In an Internet-based survey, 448 middle-aged women who reported being either perimenopausal or menopausal responded to questions about their symptoms.² Feeling tired and lacking energy were the 2 most frequently reported symptoms, in 380 (89%) and 355 (83%) of respondents, respectively. These self-selected respondents probably do not represent the menopausal population of women at large.

A prospective cohort study, using a 1-page questionnaire that included 2 fatigue scales, identified 276 (24%) of 1159 primary care patients who indicated fatigue as a major problem.³ The mean age of patients was 57 years and 66% were women. Extensive laboratory testing was not helpful in determining the cause of fatigue. The Beck Depression Inventory, the Modified Somatic Perception Questionnaire, and the Social Readjustment Rating Scale identified depression or anxiety in 80% of patients with fatigue and 12% of controls. There are no similar studies for strictly menopausal women.

The prevalence of obstructive sleep apnea and sleep-disordered breathing increases at the time of menopause and peaks at age 65.^4,5 In a retrospective chart review of patients referred for evaluation of snoring, 22 (91%) of the women with studies) were more likely to report daytime fatigue as a presenting symptom than were the 44 (55%) of men with obstructive sleep apnea (P<.01).⁶ Most striking was a sub-group (40%) of women with documented obstructive sleep apnea who reported only fatigue and morning headache but did not note apnea or restless sleep.

Coronary heart disease is the primary cause of death for women in the United States. A retrospective study of 515 women 4 to 6 months after a myocardial infarction explored self-reported symptoms.⁷ The mean age was 66±12 years and 93% were white. Unusual fatigue was the most frequent prodromal symptom experienced by 70.7% of women 1 month before a myocardial infarction, with 42.9% reporting fatigue in the acute setting. Though this retrospective study is limited both by its methodological quality and by the narrow population studied, the results suggest a gender difference between men and women in their report of symptoms of coronary artery disease.

A review of 15 studies from 1989 to 2002 reported that some studies found women were more likely to seek medical care for extreme fatigue and dyspnea than they were for chest pain. In acute coronary syndromes, 18% of women (compared with 9% of men) reported fatigue as a presenting symptom (P<.05). This review was limited by small sample sizes, retrospective chart review designs, and lack of explicitly stated critical appraisal criteria.⁸

Recommendations from others

No recommendations were identified.

Evidence summary

Studies evaluating whether menopausal women experience fatigue at higher rates than pre-or perimenopausal women are of variable quality and yield conflicting results.¹ Though several studies suggest an association between fatigue among menopausal women and disease states, poor methodology limits the strength of their findings.

In an Internet-based survey, 448 middle-aged women who reported being either perimenopausal or menopausal responded to questions about their symptoms.² Feeling tired and lacking energy were the 2 most frequently reported symptoms, in 380 (89%) and 355 (83%) of respondents, respectively. These self-selected respondents probably do not represent the menopausal population of women at large.

A prospective cohort study, using a 1-page questionnaire that included 2 fatigue scales, identified 276 (24%) of 1159 primary care patients who indicated fatigue as a major problem.³ The mean age of patients was 57 years and 66% were women. Extensive laboratory testing was not helpful in determining the cause of fatigue. The Beck Depression Inventory, the Modified Somatic Perception Questionnaire, and the Social Readjustment Rating Scale identified depression or anxiety in 80% of patients with fatigue and 12% of controls. There are no similar studies for strictly menopausal women.

The prevalence of obstructive sleep apnea and sleep-disordered breathing increases at the time of menopause and peaks at age 65.^4,5 In a retrospective chart review of patients referred for evaluation of snoring, 22 (91%) of the women with studies) were more likely to report daytime fatigue as a presenting symptom than were the 44 (55%) of men with obstructive sleep apnea (P<.01).⁶ Most striking was a sub-group (40%) of women with documented obstructive sleep apnea who reported only fatigue and morning headache but did not note apnea or restless sleep.

Coronary heart disease is the primary cause of death for women in the United States. A retrospective study of 515 women 4 to 6 months after a myocardial infarction explored self-reported symptoms.⁷ The mean age was 66±12 years and 93% were white. Unusual fatigue was the most frequent prodromal symptom experienced by 70.7% of women 1 month before a myocardial infarction, with 42.9% reporting fatigue in the acute setting. Though this retrospective study is limited both by its methodological quality and by the narrow population studied, the results suggest a gender difference between men and women in their report of symptoms of coronary artery disease.

A review of 15 studies from 1989 to 2002 reported that some studies found women were more likely to seek medical care for extreme fatigue and dyspnea than they were for chest pain. In acute coronary syndromes, 18% of women (compared with 9% of men) reported fatigue as a presenting symptom (P<.05). This review was limited by small sample sizes, retrospective chart review designs, and lack of explicitly stated critical appraisal criteria.⁸

Recommendations from others

No recommendations were identified.

Evidence summary

Studies evaluating whether menopausal women experience fatigue at higher rates than pre-or perimenopausal women are of variable quality and yield conflicting results.¹ Though several studies suggest an association between fatigue among menopausal women and disease states, poor methodology limits the strength of their findings.

In an Internet-based survey, 448 middle-aged women who reported being either perimenopausal or menopausal responded to questions about their symptoms.² Feeling tired and lacking energy were the 2 most frequently reported symptoms, in 380 (89%) and 355 (83%) of respondents, respectively. These self-selected respondents probably do not represent the menopausal population of women at large.

A prospective cohort study, using a 1-page questionnaire that included 2 fatigue scales, identified 276 (24%) of 1159 primary care patients who indicated fatigue as a major problem.³ The mean age of patients was 57 years and 66% were women. Extensive laboratory testing was not helpful in determining the cause of fatigue. The Beck Depression Inventory, the Modified Somatic Perception Questionnaire, and the Social Readjustment Rating Scale identified depression or anxiety in 80% of patients with fatigue and 12% of controls. There are no similar studies for strictly menopausal women.

The prevalence of obstructive sleep apnea and sleep-disordered breathing increases at the time of menopause and peaks at age 65.^4,5 In a retrospective chart review of patients referred for evaluation of snoring, 22 (91%) of the women with studies) were more likely to report daytime fatigue as a presenting symptom than were the 44 (55%) of men with obstructive sleep apnea (P<.01).⁶ Most striking was a sub-group (40%) of women with documented obstructive sleep apnea who reported only fatigue and morning headache but did not note apnea or restless sleep.

Coronary heart disease is the primary cause of death for women in the United States. A retrospective study of 515 women 4 to 6 months after a myocardial infarction explored self-reported symptoms.⁷ The mean age was 66±12 years and 93% were white. Unusual fatigue was the most frequent prodromal symptom experienced by 70.7% of women 1 month before a myocardial infarction, with 42.9% reporting fatigue in the acute setting. Though this retrospective study is limited both by its methodological quality and by the narrow population studied, the results suggest a gender difference between men and women in their report of symptoms of coronary artery disease.

A review of 15 studies from 1989 to 2002 reported that some studies found women were more likely to seek medical care for extreme fatigue and dyspnea than they were for chest pain. In acute coronary syndromes, 18% of women (compared with 9% of men) reported fatigue as a presenting symptom (P<.05). This review was limited by small sample sizes, retrospective chart review designs, and lack of explicitly stated critical appraisal criteria.⁸

Recommendations from others

No recommendations were identified.

Evidence summary

Public misperceptions and provider uncertainty about contraindications create missed opportunities for immunization.^1-3 The Centers for Disease Control and Prevention (CDC) defines contraindications as conditions that increase the risk of a serious reaction to vaccination. Precautions are conditions that might increase the risk of a serious reaction, or that diminish vaccine efficiency.⁴ Recommendations about contraindications and precautions for vaccine administration are partially based on studies of adverse effects (see the TABLE for common situations). Complete information on the contraindications and precautions for all common vaccinations can be accessed at www.cdc.gov/mmwr/preview/mmwrhtml/rr5102a1.htm#tab5.⁴

Data on vaccination risks are limited by a relative lack of experimental studies. Initial recommendations of the Advisory Council on Immunization Practices have been based on the findings of a 14-member Institute of Medicine (IOM) expert committee and are updated regularly.^5-7 The IOM committee reported that because vaccine-related adverse events occur infrequently, available randomized controlled trials were too small to detect differences in incidence.⁶ Much of the data come from adverse effect surveillance systems, such as the Vaccine Adverse Event Reporting System (VAERS), to which health care providers report possible adverse effects of vaccinations.

Updated contraindications by ACIP to the initial IOM recommendations have also been based on observational reports and studies.⁴ A recent Cochrane review on acellular pertussis vaccines concluded that the acellular vaccine had fewer adverse effects than the whole-cell version, but did not support any changes in contraindications or precautions.⁸

TABLE
Contraindications and precautions for vaccine administration

Recommendations from others

The ACIP recommendations serve as national standards and have been adopted by American Academy of Pediatrics and the American Academy of Family Physicians and are included in most standard reference texts.^4,9

Evidence summary

Public misperceptions and provider uncertainty about contraindications create missed opportunities for immunization.^1-3 The Centers for Disease Control and Prevention (CDC) defines contraindications as conditions that increase the risk of a serious reaction to vaccination. Precautions are conditions that might increase the risk of a serious reaction, or that diminish vaccine efficiency.⁴ Recommendations about contraindications and precautions for vaccine administration are partially based on studies of adverse effects (see the TABLE for common situations). Complete information on the contraindications and precautions for all common vaccinations can be accessed at www.cdc.gov/mmwr/preview/mmwrhtml/rr5102a1.htm#tab5.⁴

Data on vaccination risks are limited by a relative lack of experimental studies. Initial recommendations of the Advisory Council on Immunization Practices have been based on the findings of a 14-member Institute of Medicine (IOM) expert committee and are updated regularly.^5-7 The IOM committee reported that because vaccine-related adverse events occur infrequently, available randomized controlled trials were too small to detect differences in incidence.⁶ Much of the data come from adverse effect surveillance systems, such as the Vaccine Adverse Event Reporting System (VAERS), to which health care providers report possible adverse effects of vaccinations.

Updated contraindications by ACIP to the initial IOM recommendations have also been based on observational reports and studies.⁴ A recent Cochrane review on acellular pertussis vaccines concluded that the acellular vaccine had fewer adverse effects than the whole-cell version, but did not support any changes in contraindications or precautions.⁸

TABLE
Contraindications and precautions for vaccine administration

Recommendations from others

The ACIP recommendations serve as national standards and have been adopted by American Academy of Pediatrics and the American Academy of Family Physicians and are included in most standard reference texts.^4,9

Evidence summary

Public misperceptions and provider uncertainty about contraindications create missed opportunities for immunization.^1-3 The Centers for Disease Control and Prevention (CDC) defines contraindications as conditions that increase the risk of a serious reaction to vaccination. Precautions are conditions that might increase the risk of a serious reaction, or that diminish vaccine efficiency.⁴ Recommendations about contraindications and precautions for vaccine administration are partially based on studies of adverse effects (see the TABLE for common situations). Complete information on the contraindications and precautions for all common vaccinations can be accessed at www.cdc.gov/mmwr/preview/mmwrhtml/rr5102a1.htm#tab5.⁴

Data on vaccination risks are limited by a relative lack of experimental studies. Initial recommendations of the Advisory Council on Immunization Practices have been based on the findings of a 14-member Institute of Medicine (IOM) expert committee and are updated regularly.^5-7 The IOM committee reported that because vaccine-related adverse events occur infrequently, available randomized controlled trials were too small to detect differences in incidence.⁶ Much of the data come from adverse effect surveillance systems, such as the Vaccine Adverse Event Reporting System (VAERS), to which health care providers report possible adverse effects of vaccinations.

Updated contraindications by ACIP to the initial IOM recommendations have also been based on observational reports and studies.⁴ A recent Cochrane review on acellular pertussis vaccines concluded that the acellular vaccine had fewer adverse effects than the whole-cell version, but did not support any changes in contraindications or precautions.⁸

TABLE
Contraindications and precautions for vaccine administration

Recommendations from others

The ACIP recommendations serve as national standards and have been adopted by American Academy of Pediatrics and the American Academy of Family Physicians and are included in most standard reference texts.^4,9

Evidence summary

Analgesic rebound headaches are seen in 1% of the population, mostly middle-aged women with underlying migraines.^1,2 Also termed analgesic-overuse headaches, they are defined by the International Headache Society guidelines as headaches occurring more than 15 days per month, mild to moderate in intensity, developing or worsening with analgesic overuse, and resolving or reverting to the prior underlying headache pattern within 2 months of discontinuing the analgesic(s).³

A case series studied 50 patients with rebound headaches for 5 or more days a week at baseline.⁴ Patients were educated regarding analgesic overuse headaches, after which their analgesics were abruptly discontinued, and they were followed up to a year. Subcutaneous DHE was used as needed for symptomatic relief of excruciating headaches. At study completion, 78% of patients had adequately stopped analgesics. The goal of greater than 6 consecutive headache-free days was achieved in 74% patients in an average of 84 days.

A 9-week double-blind, placebo-controlled trial randomized 20 nondepressed patients with analgesic overuse headache to receive amitriptyline or active placebo (trihexyphenidyl).⁵ Patients were admitted to the hospital for 1 week and withdrawn from all analgesics. The 2 groups had similar baseline characteristics. During the hospitalization, the amitriptyline treatment group received intravenous amitriptyline escalating from 25 to 75 mg. During the following month, oral study medications were continued, and patients took low doses of aspirin or acetaminophen, as needed. There was no significant difference between the 2 groups with regard to analgesic use. At completion of this low-powered study, no difference was found between the 2 groups in headache frequency or analgesic use, although certain components of a quality-of-life scale were better in the amitriptyline group.

An open-label trial of patients with chronic migraine and analgesic overuse in a headache sub-specialty center abruptly withdrew 150 participants from analgesics and quasi-randomized them to 3 groups: prednisone (tapering from 60 to 20 mg over 6 days), naratriptan (Amerge) (2.5 mg twice daily for 6 days), or no prophylactic treatment.⁶ Patients given the active substances were told it would reduce withdrawal symptoms; patients given placebo were not given this advice. All patients received education about the pathophysiology of rebound headaches, kept a headache diary, and were phoned weekly to ensure compliance. In addition, they all received capsules containing gradually increasing doses of atenolol, nortriptyline, and flunarazine (a calcium channel blocker not FDA-approved.) Indo-methacin and chlorpromazine were used as needed. Results from the first 6 days showed no difference in headaches between the 3 groups; however, significantly more patients used chlorpromazine in the “no pharmacologic treatment” group

By the end of 5 weeks, headache frequency was significantly reduced in all groups from baseline; however, there were no differences between groups in headache frequency or intensity in this small study. Of note, there were statistically fewer withdrawal symptoms and less use of rescue medications among patients who received the initial prophylactic treatments. The indomethacin rescue use was 24%, 18%, and 14% of patients for the no prophylactic treatment, prednisone, and naratriptan groups respectively, while chlorpromazine rescue use was 14%, 0%, and 0%, respectively. The number of patients needed to treat to prevent any withdrawal symptoms (nausea, vomiting, nervousness, dizziness, etc.) was 1 for every 3.5 for naratriptan, and 6.4 for prednisone.

Recommendations from others

The American Council for Headache Education recommends discontinuing all analgesics.⁷ It notes some patients may need prophylactic medication (although no specific agent is recommended), and hospitalization may be indicated for withdrawal for patients who have abused narcotics. A headache textbook recommends 1 of 2 approaches for patients undergoing outpatient treatment: (1) gradual tapering of the offending medication with substitution of a long-acting nonsteroidal anti-inflammatory drug (NSAID) and initiation of preventive therapy, or (2) abrupt discontinuation of the offending medication and initiation followed by gradual tapering of a “transitional” medication such as NSAIDs, DHE, corticosteroids, or triptans. The authors recommend an intravenous DHE protocol for treatment failures and patients requiring inpatient treatment.⁸

Evidence summary

Analgesic rebound headaches are seen in 1% of the population, mostly middle-aged women with underlying migraines.^1,2 Also termed analgesic-overuse headaches, they are defined by the International Headache Society guidelines as headaches occurring more than 15 days per month, mild to moderate in intensity, developing or worsening with analgesic overuse, and resolving or reverting to the prior underlying headache pattern within 2 months of discontinuing the analgesic(s).³

A case series studied 50 patients with rebound headaches for 5 or more days a week at baseline.⁴ Patients were educated regarding analgesic overuse headaches, after which their analgesics were abruptly discontinued, and they were followed up to a year. Subcutaneous DHE was used as needed for symptomatic relief of excruciating headaches. At study completion, 78% of patients had adequately stopped analgesics. The goal of greater than 6 consecutive headache-free days was achieved in 74% patients in an average of 84 days.

A 9-week double-blind, placebo-controlled trial randomized 20 nondepressed patients with analgesic overuse headache to receive amitriptyline or active placebo (trihexyphenidyl).⁵ Patients were admitted to the hospital for 1 week and withdrawn from all analgesics. The 2 groups had similar baseline characteristics. During the hospitalization, the amitriptyline treatment group received intravenous amitriptyline escalating from 25 to 75 mg. During the following month, oral study medications were continued, and patients took low doses of aspirin or acetaminophen, as needed. There was no significant difference between the 2 groups with regard to analgesic use. At completion of this low-powered study, no difference was found between the 2 groups in headache frequency or analgesic use, although certain components of a quality-of-life scale were better in the amitriptyline group.

An open-label trial of patients with chronic migraine and analgesic overuse in a headache sub-specialty center abruptly withdrew 150 participants from analgesics and quasi-randomized them to 3 groups: prednisone (tapering from 60 to 20 mg over 6 days), naratriptan (Amerge) (2.5 mg twice daily for 6 days), or no prophylactic treatment.⁶ Patients given the active substances were told it would reduce withdrawal symptoms; patients given placebo were not given this advice. All patients received education about the pathophysiology of rebound headaches, kept a headache diary, and were phoned weekly to ensure compliance. In addition, they all received capsules containing gradually increasing doses of atenolol, nortriptyline, and flunarazine (a calcium channel blocker not FDA-approved.) Indo-methacin and chlorpromazine were used as needed. Results from the first 6 days showed no difference in headaches between the 3 groups; however, significantly more patients used chlorpromazine in the “no pharmacologic treatment” group

By the end of 5 weeks, headache frequency was significantly reduced in all groups from baseline; however, there were no differences between groups in headache frequency or intensity in this small study. Of note, there were statistically fewer withdrawal symptoms and less use of rescue medications among patients who received the initial prophylactic treatments. The indomethacin rescue use was 24%, 18%, and 14% of patients for the no prophylactic treatment, prednisone, and naratriptan groups respectively, while chlorpromazine rescue use was 14%, 0%, and 0%, respectively. The number of patients needed to treat to prevent any withdrawal symptoms (nausea, vomiting, nervousness, dizziness, etc.) was 1 for every 3.5 for naratriptan, and 6.4 for prednisone.

Recommendations from others

The American Council for Headache Education recommends discontinuing all analgesics.⁷ It notes some patients may need prophylactic medication (although no specific agent is recommended), and hospitalization may be indicated for withdrawal for patients who have abused narcotics. A headache textbook recommends 1 of 2 approaches for patients undergoing outpatient treatment: (1) gradual tapering of the offending medication with substitution of a long-acting nonsteroidal anti-inflammatory drug (NSAID) and initiation of preventive therapy, or (2) abrupt discontinuation of the offending medication and initiation followed by gradual tapering of a “transitional” medication such as NSAIDs, DHE, corticosteroids, or triptans. The authors recommend an intravenous DHE protocol for treatment failures and patients requiring inpatient treatment.⁸

Evidence summary

Analgesic rebound headaches are seen in 1% of the population, mostly middle-aged women with underlying migraines.^1,2 Also termed analgesic-overuse headaches, they are defined by the International Headache Society guidelines as headaches occurring more than 15 days per month, mild to moderate in intensity, developing or worsening with analgesic overuse, and resolving or reverting to the prior underlying headache pattern within 2 months of discontinuing the analgesic(s).³

A case series studied 50 patients with rebound headaches for 5 or more days a week at baseline.⁴ Patients were educated regarding analgesic overuse headaches, after which their analgesics were abruptly discontinued, and they were followed up to a year. Subcutaneous DHE was used as needed for symptomatic relief of excruciating headaches. At study completion, 78% of patients had adequately stopped analgesics. The goal of greater than 6 consecutive headache-free days was achieved in 74% patients in an average of 84 days.

A 9-week double-blind, placebo-controlled trial randomized 20 nondepressed patients with analgesic overuse headache to receive amitriptyline or active placebo (trihexyphenidyl).⁵ Patients were admitted to the hospital for 1 week and withdrawn from all analgesics. The 2 groups had similar baseline characteristics. During the hospitalization, the amitriptyline treatment group received intravenous amitriptyline escalating from 25 to 75 mg. During the following month, oral study medications were continued, and patients took low doses of aspirin or acetaminophen, as needed. There was no significant difference between the 2 groups with regard to analgesic use. At completion of this low-powered study, no difference was found between the 2 groups in headache frequency or analgesic use, although certain components of a quality-of-life scale were better in the amitriptyline group.

An open-label trial of patients with chronic migraine and analgesic overuse in a headache sub-specialty center abruptly withdrew 150 participants from analgesics and quasi-randomized them to 3 groups: prednisone (tapering from 60 to 20 mg over 6 days), naratriptan (Amerge) (2.5 mg twice daily for 6 days), or no prophylactic treatment.⁶ Patients given the active substances were told it would reduce withdrawal symptoms; patients given placebo were not given this advice. All patients received education about the pathophysiology of rebound headaches, kept a headache diary, and were phoned weekly to ensure compliance. In addition, they all received capsules containing gradually increasing doses of atenolol, nortriptyline, and flunarazine (a calcium channel blocker not FDA-approved.) Indo-methacin and chlorpromazine were used as needed. Results from the first 6 days showed no difference in headaches between the 3 groups; however, significantly more patients used chlorpromazine in the “no pharmacologic treatment” group

By the end of 5 weeks, headache frequency was significantly reduced in all groups from baseline; however, there were no differences between groups in headache frequency or intensity in this small study. Of note, there were statistically fewer withdrawal symptoms and less use of rescue medications among patients who received the initial prophylactic treatments. The indomethacin rescue use was 24%, 18%, and 14% of patients for the no prophylactic treatment, prednisone, and naratriptan groups respectively, while chlorpromazine rescue use was 14%, 0%, and 0%, respectively. The number of patients needed to treat to prevent any withdrawal symptoms (nausea, vomiting, nervousness, dizziness, etc.) was 1 for every 3.5 for naratriptan, and 6.4 for prednisone.

Recommendations from others

The American Council for Headache Education recommends discontinuing all analgesics.⁷ It notes some patients may need prophylactic medication (although no specific agent is recommended), and hospitalization may be indicated for withdrawal for patients who have abused narcotics. A headache textbook recommends 1 of 2 approaches for patients undergoing outpatient treatment: (1) gradual tapering of the offending medication with substitution of a long-acting nonsteroidal anti-inflammatory drug (NSAID) and initiation of preventive therapy, or (2) abrupt discontinuation of the offending medication and initiation followed by gradual tapering of a “transitional” medication such as NSAIDs, DHE, corticosteroids, or triptans. The authors recommend an intravenous DHE protocol for treatment failures and patients requiring inpatient treatment.⁸

Evidence Summary

The subjects of most ADHD medication studies have been school-age children. Most children with ADHD will have symptoms persisting into teenage years, and methylphenidate has been increasingly prescribed for them.^1,2 Various systematic reviews and meta-analyses have demonstrated the effectiveness of short-term methylphenidate in the treatment of adolescents with ADHD.^3-5 Most participants in these studies are males aged <13 years. Therefore, any conclusions about the effectiveness of methylphenidate in older adolescents must be inferred.

The most comprehensive systematic review found 8 well-controlled crossover trials with an average sample size of 24.8 (range, 9–48).⁶ The average duration of the studies was 6 weeks. The majority of the participants were white males with a mean age of 13 years. Each study showed statistically significant improvement from treatment with methylphenidate. Average effect sizes were calculated for 3 domains: ADHD symptoms (0.94), social behavior (1.06), and academic performance (1.25). Effect sizes were calculated using a modified Cohen’s d, which is the difference between the treated and untreated means divided by the standard deviation in the untreated condition. It is difficult to translate these changes in effect size into clinically meaningful outcome measures, although one rule of thumb estimates an effect size of 0.8 is moderate to large.

Of the 3 studies that reported the proportion of subjects with clinically significant improvement, the modal result was about one half showings improvement with methylphenidate. Of trials assessing dosing levels, <50% found significant differences between “low” and “high” doses. However, the researchers did not give their definition of low and high doses. Also, diminishing clinical improvement was noted with higher methylphenidate doses.

A single study on the once-daily stimulant preparation, extended-release methylphenidate, shows statistically significant improvement in adolescent ADHD.⁷ In this multicenter, randomized, double-blind, placebo-controlled trial of 177 adolescents, subjects were given placebo (n=87) or extended-release methylphenidate (n=90) at titrated doses from 18 mg/d to 72 mg/d. Following a subsequent 2-week randomization phase, clinical investigators found extended-release methylphenidate significantly superior to placebo (P=.001) on the ADHD scale. Subjects also rated it significantly superior to placebo (P=.001) on the Conners-Wells’ Self-Report Scale. Mean dose and average age were not reported. This study has been presented as an abstract and is not yet published.

Recommendations from others

The American Academy of Child and Adolescent Psychiatry (AACAP) supports the prescribing of methylphenidate in adolescents with ADHD.⁸ Given the unique psychosocial, environmental, and scheduling challenges of adolescence, the AACAP mentions extended-release methylphenidate as “well-suited for treatment of adolescents.”

Evidence Summary

The subjects of most ADHD medication studies have been school-age children. Most children with ADHD will have symptoms persisting into teenage years, and methylphenidate has been increasingly prescribed for them.^1,2 Various systematic reviews and meta-analyses have demonstrated the effectiveness of short-term methylphenidate in the treatment of adolescents with ADHD.^3-5 Most participants in these studies are males aged <13 years. Therefore, any conclusions about the effectiveness of methylphenidate in older adolescents must be inferred.

The most comprehensive systematic review found 8 well-controlled crossover trials with an average sample size of 24.8 (range, 9–48).⁶ The average duration of the studies was 6 weeks. The majority of the participants were white males with a mean age of 13 years. Each study showed statistically significant improvement from treatment with methylphenidate. Average effect sizes were calculated for 3 domains: ADHD symptoms (0.94), social behavior (1.06), and academic performance (1.25). Effect sizes were calculated using a modified Cohen’s d, which is the difference between the treated and untreated means divided by the standard deviation in the untreated condition. It is difficult to translate these changes in effect size into clinically meaningful outcome measures, although one rule of thumb estimates an effect size of 0.8 is moderate to large.

Of the 3 studies that reported the proportion of subjects with clinically significant improvement, the modal result was about one half showings improvement with methylphenidate. Of trials assessing dosing levels, <50% found significant differences between “low” and “high” doses. However, the researchers did not give their definition of low and high doses. Also, diminishing clinical improvement was noted with higher methylphenidate doses.

A single study on the once-daily stimulant preparation, extended-release methylphenidate, shows statistically significant improvement in adolescent ADHD.⁷ In this multicenter, randomized, double-blind, placebo-controlled trial of 177 adolescents, subjects were given placebo (n=87) or extended-release methylphenidate (n=90) at titrated doses from 18 mg/d to 72 mg/d. Following a subsequent 2-week randomization phase, clinical investigators found extended-release methylphenidate significantly superior to placebo (P=.001) on the ADHD scale. Subjects also rated it significantly superior to placebo (P=.001) on the Conners-Wells’ Self-Report Scale. Mean dose and average age were not reported. This study has been presented as an abstract and is not yet published.

Recommendations from others

The American Academy of Child and Adolescent Psychiatry (AACAP) supports the prescribing of methylphenidate in adolescents with ADHD.⁸ Given the unique psychosocial, environmental, and scheduling challenges of adolescence, the AACAP mentions extended-release methylphenidate as “well-suited for treatment of adolescents.”

Evidence Summary

The subjects of most ADHD medication studies have been school-age children. Most children with ADHD will have symptoms persisting into teenage years, and methylphenidate has been increasingly prescribed for them.^1,2 Various systematic reviews and meta-analyses have demonstrated the effectiveness of short-term methylphenidate in the treatment of adolescents with ADHD.^3-5 Most participants in these studies are males aged <13 years. Therefore, any conclusions about the effectiveness of methylphenidate in older adolescents must be inferred.

The most comprehensive systematic review found 8 well-controlled crossover trials with an average sample size of 24.8 (range, 9–48).⁶ The average duration of the studies was 6 weeks. The majority of the participants were white males with a mean age of 13 years. Each study showed statistically significant improvement from treatment with methylphenidate. Average effect sizes were calculated for 3 domains: ADHD symptoms (0.94), social behavior (1.06), and academic performance (1.25). Effect sizes were calculated using a modified Cohen’s d, which is the difference between the treated and untreated means divided by the standard deviation in the untreated condition. It is difficult to translate these changes in effect size into clinically meaningful outcome measures, although one rule of thumb estimates an effect size of 0.8 is moderate to large.

Of the 3 studies that reported the proportion of subjects with clinically significant improvement, the modal result was about one half showings improvement with methylphenidate. Of trials assessing dosing levels, <50% found significant differences between “low” and “high” doses. However, the researchers did not give their definition of low and high doses. Also, diminishing clinical improvement was noted with higher methylphenidate doses.

A single study on the once-daily stimulant preparation, extended-release methylphenidate, shows statistically significant improvement in adolescent ADHD.⁷ In this multicenter, randomized, double-blind, placebo-controlled trial of 177 adolescents, subjects were given placebo (n=87) or extended-release methylphenidate (n=90) at titrated doses from 18 mg/d to 72 mg/d. Following a subsequent 2-week randomization phase, clinical investigators found extended-release methylphenidate significantly superior to placebo (P=.001) on the ADHD scale. Subjects also rated it significantly superior to placebo (P=.001) on the Conners-Wells’ Self-Report Scale. Mean dose and average age were not reported. This study has been presented as an abstract and is not yet published.

Recommendations from others

The American Academy of Child and Adolescent Psychiatry (AACAP) supports the prescribing of methylphenidate in adolescents with ADHD.⁸ Given the unique psychosocial, environmental, and scheduling challenges of adolescence, the AACAP mentions extended-release methylphenidate as “well-suited for treatment of adolescents.”

EVIDENCE-BASED ANSWER

Healthy, unimmunized children who have not had varicella infection should be vaccinated (strength of recommendation: A, based on randomized controlled trials). Use of the vaccine in immunocompromised children is still being studied and has not been approved by the Food and Drug Administration (FDA).

Evidence summary

Before the introduction of the varicella vaccine, almost 4 million cases of chickenpox occurred each year in the United States, resulting in 11,000 hospitalizations and 100 deaths.¹ Varicella is the leading cause of vaccine-preventable death in children.²

In a search of the literature from 1966 to 2000, a systematic review identified 24 randomized controlled trials and 18 cohort studies of varicella vaccination.³ In children aged 10 months to 14 years, 1 randomized controlled trial found protective efficacy of 100% over 9 months and 98% over 7 years.⁴ A second trial showed efficacy of 72% over 29 months.⁵Cohort studies of children report that the vaccine is 84% to 86% effective in preventing varicella and 100% effective in preventing moderate to severe infections.³

Cumulative results of all studies show the number needed to vaccinate to prevent 1 case of varicella ranges from 5.5 to 11.8, and the number needed to prevent 1 complicated case ranges from 550 to 1180.

No direct evidence supports or refutes a reduction in varicella mortality or rates of hospitalization due to vaccination. Randomized controlled trials show no increase in rates of fever or rash among those receiving vaccine; however, cohort studies report fever (0%–36%), local injection site reactions (7%–30%), and rash (5%).³ No clinical trials have shown transmission of vaccine-related varicella zoster virus in immunocompetent patients, and only 3 proven cases of transmission of vaccine virus to susceptible contacts have been documented.⁶ Some evidence suggests the incidence of herpes zoster is reduced in immunocompromised vaccine recipients, but long-term observation is needed to assess the effect on healthy recipients.⁷

One concern about the vaccine is that waning immunity over time could result in increased incidence of varicella infection during adulthood. While existing studies document persistence of antibodies for up to 20 years following immunization,³ long-term effectiveness should continue to be monitored.

The FDA has not approved this live-virus vaccine for use in pregnant women and immunocom-promised persons, including transplant recipients and persons receiving corticosteroid therapy. However, the vaccine has been very well-studied in children with leukemia. A review of these studies found that optimal seroconversion requires 2 sequential vaccine doses (86% efficacy). A rash of varying severity was the predominant adverse event in 20% to 50% of vacinees.⁷ Study of vaccine use in other immunocompromised children has been limited. Early results from a trial in HIV-infected children who were not severely immunocompromised suggests similar tolerance and efficacy compared with children without HIV.⁸ A systemic review of cost-effectiveness of varicella vaccine is based predominantly on mathematical models.⁹These models show societal savings due to decrease in unproductive days for parents, but fail to demonstrate actual healthcare savings.

Recommendations from others

The American Academy of Pediatrics (AAP), Advisory Committee on Immunization Practices (ACIP), and American Academy of Family Medicine all recommend vaccinating unimmunized children aged 12 months and older who have not had varicella infection, and not vaccinating children with cellular immunodeficiencies.^2,10,11 The AAP suggests the vaccine could be considered for children with acute lymphocytic leukemia and for HIV-infected children with mild or no signs or symptoms. The ACIP guidelines are similar, with the addition that children with impaired humoral immunity may now be vaccinated.

EVIDENCE-BASED ANSWER

Healthy, unimmunized children who have not had varicella infection should be vaccinated (strength of recommendation: A, based on randomized controlled trials). Use of the vaccine in immunocompromised children is still being studied and has not been approved by the Food and Drug Administration (FDA).

Evidence summary

Before the introduction of the varicella vaccine, almost 4 million cases of chickenpox occurred each year in the United States, resulting in 11,000 hospitalizations and 100 deaths.¹ Varicella is the leading cause of vaccine-preventable death in children.²

In a search of the literature from 1966 to 2000, a systematic review identified 24 randomized controlled trials and 18 cohort studies of varicella vaccination.³ In children aged 10 months to 14 years, 1 randomized controlled trial found protective efficacy of 100% over 9 months and 98% over 7 years.⁴ A second trial showed efficacy of 72% over 29 months.⁵Cohort studies of children report that the vaccine is 84% to 86% effective in preventing varicella and 100% effective in preventing moderate to severe infections.³

Cumulative results of all studies show the number needed to vaccinate to prevent 1 case of varicella ranges from 5.5 to 11.8, and the number needed to prevent 1 complicated case ranges from 550 to 1180.

No direct evidence supports or refutes a reduction in varicella mortality or rates of hospitalization due to vaccination. Randomized controlled trials show no increase in rates of fever or rash among those receiving vaccine; however, cohort studies report fever (0%–36%), local injection site reactions (7%–30%), and rash (5%).³ No clinical trials have shown transmission of vaccine-related varicella zoster virus in immunocompetent patients, and only 3 proven cases of transmission of vaccine virus to susceptible contacts have been documented.⁶ Some evidence suggests the incidence of herpes zoster is reduced in immunocompromised vaccine recipients, but long-term observation is needed to assess the effect on healthy recipients.⁷

One concern about the vaccine is that waning immunity over time could result in increased incidence of varicella infection during adulthood. While existing studies document persistence of antibodies for up to 20 years following immunization,³ long-term effectiveness should continue to be monitored.

The FDA has not approved this live-virus vaccine for use in pregnant women and immunocom-promised persons, including transplant recipients and persons receiving corticosteroid therapy. However, the vaccine has been very well-studied in children with leukemia. A review of these studies found that optimal seroconversion requires 2 sequential vaccine doses (86% efficacy). A rash of varying severity was the predominant adverse event in 20% to 50% of vacinees.⁷ Study of vaccine use in other immunocompromised children has been limited. Early results from a trial in HIV-infected children who were not severely immunocompromised suggests similar tolerance and efficacy compared with children without HIV.⁸ A systemic review of cost-effectiveness of varicella vaccine is based predominantly on mathematical models.⁹These models show societal savings due to decrease in unproductive days for parents, but fail to demonstrate actual healthcare savings.

Recommendations from others

The American Academy of Pediatrics (AAP), Advisory Committee on Immunization Practices (ACIP), and American Academy of Family Medicine all recommend vaccinating unimmunized children aged 12 months and older who have not had varicella infection, and not vaccinating children with cellular immunodeficiencies.^2,10,11 The AAP suggests the vaccine could be considered for children with acute lymphocytic leukemia and for HIV-infected children with mild or no signs or symptoms. The ACIP guidelines are similar, with the addition that children with impaired humoral immunity may now be vaccinated.

EVIDENCE-BASED ANSWER

Healthy, unimmunized children who have not had varicella infection should be vaccinated (strength of recommendation: A, based on randomized controlled trials). Use of the vaccine in immunocompromised children is still being studied and has not been approved by the Food and Drug Administration (FDA).

Evidence summary

Before the introduction of the varicella vaccine, almost 4 million cases of chickenpox occurred each year in the United States, resulting in 11,000 hospitalizations and 100 deaths.¹ Varicella is the leading cause of vaccine-preventable death in children.²

In a search of the literature from 1966 to 2000, a systematic review identified 24 randomized controlled trials and 18 cohort studies of varicella vaccination.³ In children aged 10 months to 14 years, 1 randomized controlled trial found protective efficacy of 100% over 9 months and 98% over 7 years.⁴ A second trial showed efficacy of 72% over 29 months.⁵Cohort studies of children report that the vaccine is 84% to 86% effective in preventing varicella and 100% effective in preventing moderate to severe infections.³

Cumulative results of all studies show the number needed to vaccinate to prevent 1 case of varicella ranges from 5.5 to 11.8, and the number needed to prevent 1 complicated case ranges from 550 to 1180.

No direct evidence supports or refutes a reduction in varicella mortality or rates of hospitalization due to vaccination. Randomized controlled trials show no increase in rates of fever or rash among those receiving vaccine; however, cohort studies report fever (0%–36%), local injection site reactions (7%–30%), and rash (5%).³ No clinical trials have shown transmission of vaccine-related varicella zoster virus in immunocompetent patients, and only 3 proven cases of transmission of vaccine virus to susceptible contacts have been documented.⁶ Some evidence suggests the incidence of herpes zoster is reduced in immunocompromised vaccine recipients, but long-term observation is needed to assess the effect on healthy recipients.⁷

One concern about the vaccine is that waning immunity over time could result in increased incidence of varicella infection during adulthood. While existing studies document persistence of antibodies for up to 20 years following immunization,³ long-term effectiveness should continue to be monitored.

The FDA has not approved this live-virus vaccine for use in pregnant women and immunocom-promised persons, including transplant recipients and persons receiving corticosteroid therapy. However, the vaccine has been very well-studied in children with leukemia. A review of these studies found that optimal seroconversion requires 2 sequential vaccine doses (86% efficacy). A rash of varying severity was the predominant adverse event in 20% to 50% of vacinees.⁷ Study of vaccine use in other immunocompromised children has been limited. Early results from a trial in HIV-infected children who were not severely immunocompromised suggests similar tolerance and efficacy compared with children without HIV.⁸ A systemic review of cost-effectiveness of varicella vaccine is based predominantly on mathematical models.⁹These models show societal savings due to decrease in unproductive days for parents, but fail to demonstrate actual healthcare savings.

Recommendations from others

The American Academy of Pediatrics (AAP), Advisory Committee on Immunization Practices (ACIP), and American Academy of Family Medicine all recommend vaccinating unimmunized children aged 12 months and older who have not had varicella infection, and not vaccinating children with cellular immunodeficiencies.^2,10,11 The AAP suggests the vaccine could be considered for children with acute lymphocytic leukemia and for HIV-infected children with mild or no signs or symptoms. The ACIP guidelines are similar, with the addition that children with impaired humoral immunity may now be vaccinated.

Evidence summary

Because of the significant inflammatory sequelae of PID, it is the standard of care to treat women with suggestive signs and symptoms. Clinical diagnosis has a positive predictive value of 65% to 90% compared with laparoscopy.¹ While no single test is both sensitive and specific, a combination of biochemical tests for inflammation may improve the ability to rule out PID.

A prospective cohort study of 120 women presenting to an ambulatory center with symptoms of PID evaluated the tests commonly used to support the clinical diagnosis of PID.² The objective criteria used for diagnosis included histologic evidence of acute endometritis via endometrial biopsy, purulent exudates in the pelvis on laparoscopy, or microbiologic evidence of Neisseris gonorrhea or Chlamydia trachomatis from the upper genital tract. The Table shows the sensitivities, specificities, and predictive values for an elevated white blood cells (>10,000/mm), ESR (>15 mm/hr), CRP (>5 mg/dL), and increased vaginal white blood cells (>3 white blood cells/high-power field) for detection of PID. If all 4 test results are negative, PID is reliably ruled out with a sensitivity of 100%. These results may be an overestimate, as the gold standard was not uniformly applied.

The role of CRP and ESR in the diagnosis of acute PID was studied in 41 women with clinically suspected acute PID who presented to a university department of obstetrics and gynecology.³ Women underwent laparoscopy, endometrial sampling, and cultures of the upper genital tract to confirm the diagnosis. When considered together, a positive value in either the ESR (cutoff level of 15 mm/hr) or CRP (cutoff >20 mg/dL) had a sensitivity of 91% and a specificity of 50%.

Another report looked at the ability of ESR and CRP to differentiate between mild, moderate, and severe PID in 72 women undergoing laparoscopy at a university department of gynecology.⁴ The cutoff levels were ESR >40 mm/hr and CRP >60 mg/dL. If either test was abnormal, the sensitivity and the negative predictive value for severe disease were 97% and 96%, respectively ( Table). All patients with tuboovarian abscess or perihepatitis and 6 of 7 patients who had anaerobic bacteria isolated from the fallopian tubes tested positive with these cutoff levels.

A meta-analysis from 1991 found 12 studies, not including any of the above studies, and assessed the laboratory criteria for the diagnosis of PID. No single or combination diagnostic indicator was found to reliably predict PID. However, the CRP and the ESR were useful in ruling out PID, with good sensitivities for CRP in 4 of 4 studies analyzed (74%–93%) and for the ESR in 4 of 6 studies (64%–81%). Ten of 12 studies used laparoscopy as the gold standard.⁵

TABLE
Diagnostic performance of blood tests for pelvic inflammatory disease

Recommendations from others

The Centers for Disease Control and Prevention makes no specific recommendation for the use of specific blood tests in the diagnosis of PID.¹ The Association for Genitourinary Medicine states that an elevated ESR or CRP supports the diagnosis of PID.⁶

Evidence summary

Because of the significant inflammatory sequelae of PID, it is the standard of care to treat women with suggestive signs and symptoms. Clinical diagnosis has a positive predictive value of 65% to 90% compared with laparoscopy.¹ While no single test is both sensitive and specific, a combination of biochemical tests for inflammation may improve the ability to rule out PID.

A prospective cohort study of 120 women presenting to an ambulatory center with symptoms of PID evaluated the tests commonly used to support the clinical diagnosis of PID.² The objective criteria used for diagnosis included histologic evidence of acute endometritis via endometrial biopsy, purulent exudates in the pelvis on laparoscopy, or microbiologic evidence of Neisseris gonorrhea or Chlamydia trachomatis from the upper genital tract. The Table shows the sensitivities, specificities, and predictive values for an elevated white blood cells (>10,000/mm), ESR (>15 mm/hr), CRP (>5 mg/dL), and increased vaginal white blood cells (>3 white blood cells/high-power field) for detection of PID. If all 4 test results are negative, PID is reliably ruled out with a sensitivity of 100%. These results may be an overestimate, as the gold standard was not uniformly applied.

The role of CRP and ESR in the diagnosis of acute PID was studied in 41 women with clinically suspected acute PID who presented to a university department of obstetrics and gynecology.³ Women underwent laparoscopy, endometrial sampling, and cultures of the upper genital tract to confirm the diagnosis. When considered together, a positive value in either the ESR (cutoff level of 15 mm/hr) or CRP (cutoff >20 mg/dL) had a sensitivity of 91% and a specificity of 50%.

Another report looked at the ability of ESR and CRP to differentiate between mild, moderate, and severe PID in 72 women undergoing laparoscopy at a university department of gynecology.⁴ The cutoff levels were ESR >40 mm/hr and CRP >60 mg/dL. If either test was abnormal, the sensitivity and the negative predictive value for severe disease were 97% and 96%, respectively ( Table). All patients with tuboovarian abscess or perihepatitis and 6 of 7 patients who had anaerobic bacteria isolated from the fallopian tubes tested positive with these cutoff levels.

A meta-analysis from 1991 found 12 studies, not including any of the above studies, and assessed the laboratory criteria for the diagnosis of PID. No single or combination diagnostic indicator was found to reliably predict PID. However, the CRP and the ESR were useful in ruling out PID, with good sensitivities for CRP in 4 of 4 studies analyzed (74%–93%) and for the ESR in 4 of 6 studies (64%–81%). Ten of 12 studies used laparoscopy as the gold standard.⁵

TABLE
Diagnostic performance of blood tests for pelvic inflammatory disease

Recommendations from others

The Centers for Disease Control and Prevention makes no specific recommendation for the use of specific blood tests in the diagnosis of PID.¹ The Association for Genitourinary Medicine states that an elevated ESR or CRP supports the diagnosis of PID.⁶

Evidence summary

Because of the significant inflammatory sequelae of PID, it is the standard of care to treat women with suggestive signs and symptoms. Clinical diagnosis has a positive predictive value of 65% to 90% compared with laparoscopy.¹ While no single test is both sensitive and specific, a combination of biochemical tests for inflammation may improve the ability to rule out PID.

A prospective cohort study of 120 women presenting to an ambulatory center with symptoms of PID evaluated the tests commonly used to support the clinical diagnosis of PID.² The objective criteria used for diagnosis included histologic evidence of acute endometritis via endometrial biopsy, purulent exudates in the pelvis on laparoscopy, or microbiologic evidence of Neisseris gonorrhea or Chlamydia trachomatis from the upper genital tract. The Table shows the sensitivities, specificities, and predictive values for an elevated white blood cells (>10,000/mm), ESR (>15 mm/hr), CRP (>5 mg/dL), and increased vaginal white blood cells (>3 white blood cells/high-power field) for detection of PID. If all 4 test results are negative, PID is reliably ruled out with a sensitivity of 100%. These results may be an overestimate, as the gold standard was not uniformly applied.

The role of CRP and ESR in the diagnosis of acute PID was studied in 41 women with clinically suspected acute PID who presented to a university department of obstetrics and gynecology.³ Women underwent laparoscopy, endometrial sampling, and cultures of the upper genital tract to confirm the diagnosis. When considered together, a positive value in either the ESR (cutoff level of 15 mm/hr) or CRP (cutoff >20 mg/dL) had a sensitivity of 91% and a specificity of 50%.

Another report looked at the ability of ESR and CRP to differentiate between mild, moderate, and severe PID in 72 women undergoing laparoscopy at a university department of gynecology.⁴ The cutoff levels were ESR >40 mm/hr and CRP >60 mg/dL. If either test was abnormal, the sensitivity and the negative predictive value for severe disease were 97% and 96%, respectively ( Table). All patients with tuboovarian abscess or perihepatitis and 6 of 7 patients who had anaerobic bacteria isolated from the fallopian tubes tested positive with these cutoff levels.

A meta-analysis from 1991 found 12 studies, not including any of the above studies, and assessed the laboratory criteria for the diagnosis of PID. No single or combination diagnostic indicator was found to reliably predict PID. However, the CRP and the ESR were useful in ruling out PID, with good sensitivities for CRP in 4 of 4 studies analyzed (74%–93%) and for the ESR in 4 of 6 studies (64%–81%). Ten of 12 studies used laparoscopy as the gold standard.⁵

TABLE
Diagnostic performance of blood tests for pelvic inflammatory disease

Recommendations from others

The Centers for Disease Control and Prevention makes no specific recommendation for the use of specific blood tests in the diagnosis of PID.¹ The Association for Genitourinary Medicine states that an elevated ESR or CRP supports the diagnosis of PID.⁶

Evidence summary

A well-done systematic review of 12 trials assessing the efficacy of stimulant therapy in the treatment of adult ADHD did not find sufficient evidence that stimulants were effective.¹ Significant heterogeneity and poor reporting of methodology was seen among the studies.

The 1 study rated as high-quality was a 7-week randomized controlled trial using a crossover comparison of methylphenidate and placebo.² There was a favorable response in 78% (18/23) of subjects while takin methylphenidate, in contrast to 4% (1/23) while taking placebo (number needed to treat [NNT]=1.4; P<.0001). A favorable response was assessed by the Clinical Global Impression Scale, a measure of illness severity and improvement, and a >30% reduction in symptoms as measured by the ADHD Rating Scale. A more recent, but less rigorous, systematic review identified 15 studies of stimulant efficacy in adults.³ Researchers concluded that under controlled conditions, stimulants are efficacious in the treatment of ADHD in adults. The rate of response among the studies ranged from 25% to 78%.

One of the better studies in this review was a randomized, double-blind, 3-phase crossover study of dextroamphetamine, modafinil (a drug used to treat narcolepsy), and placebo.⁴ Each phase was 2 weeks long, with a 4-day washout in between. A favorable response was defined as a reduction of ADHD symptoms by at least 30% on the DSM-IV ADHD Behavior Checklist for Adults. Dextroamphetamine and modafinil showed the same response rate in 10 of 21 patients. Both treatments had a significant improvement over placebo (P<.001). It was unclear from the study what percentage of subjects responded to placebo.

A similar study compared dextroamphetamine, guanfacine (an antihypertensive agent), and placebo in 17 patients.⁵ On the DSM-IV ADHD Behavior Checklist for Adults, subjects taking dextroamphetamine or guanfacine reported similar decreases in mean ADHD scores compared with placebo (24 vs 22 vs 30; P<.05). They did not report the number of subjects who had a 30% reduction in symptoms. Of note: at the end of the study but prior to unblinding, subjects were asked which medication they preferred. Twelve subjects chose dextroamphetamine, 4 chose guanfacine, and 1 chose placebo. Subjects’ stated reason for choosing dextroamphetamine was the positive effect it had on their motivation.

Another study included in this review was a randomized controlled trial of mixed amphetamine salts. Of the 27 adults who completed the study, 19 (70%) responded favorably to mixed amphetamine salts compared with 2 (7.4%) receiving placebo (NNT=1.6; P<.001).⁶ Favorable response was defined as more than a 30% reduction of symptoms on the ADHD Rating Scale. Not included in either review was a 7-week randomized controlled trial comparing methylphenidate with sustained-release buproprion.⁷ Thirty out of 37 subjects completed at least 1 week of the study. The primary indicator of a favorable response was the Clinical Global Impression Scale. The rate of response was 50% for methylphenidate, 64% for sustained-release buproprion, and 27% for placebo (P<.14).

Recommendations from others

The American Academy of Child and Adolescent Psychiatry⁸ concluded that stimulant medication can be used to treat adults who have been carefully evaluated. They recommend starting methylphenidate, dextroamphetamine, or mixed amphetamine salts according to patient and clinician preference (Table). They do not recommend the use of pemoline due to the potential for hepatic failure.

TABLE
Stimulants used to treat ADHD in adults

Evidence summary

A well-done systematic review of 12 trials assessing the efficacy of stimulant therapy in the treatment of adult ADHD did not find sufficient evidence that stimulants were effective.¹ Significant heterogeneity and poor reporting of methodology was seen among the studies.

The 1 study rated as high-quality was a 7-week randomized controlled trial using a crossover comparison of methylphenidate and placebo.² There was a favorable response in 78% (18/23) of subjects while takin methylphenidate, in contrast to 4% (1/23) while taking placebo (number needed to treat [NNT]=1.4; P<.0001). A favorable response was assessed by the Clinical Global Impression Scale, a measure of illness severity and improvement, and a >30% reduction in symptoms as measured by the ADHD Rating Scale. A more recent, but less rigorous, systematic review identified 15 studies of stimulant efficacy in adults.³ Researchers concluded that under controlled conditions, stimulants are efficacious in the treatment of ADHD in adults. The rate of response among the studies ranged from 25% to 78%.

One of the better studies in this review was a randomized, double-blind, 3-phase crossover study of dextroamphetamine, modafinil (a drug used to treat narcolepsy), and placebo.⁴ Each phase was 2 weeks long, with a 4-day washout in between. A favorable response was defined as a reduction of ADHD symptoms by at least 30% on the DSM-IV ADHD Behavior Checklist for Adults. Dextroamphetamine and modafinil showed the same response rate in 10 of 21 patients. Both treatments had a significant improvement over placebo (P<.001). It was unclear from the study what percentage of subjects responded to placebo.

A similar study compared dextroamphetamine, guanfacine (an antihypertensive agent), and placebo in 17 patients.⁵ On the DSM-IV ADHD Behavior Checklist for Adults, subjects taking dextroamphetamine or guanfacine reported similar decreases in mean ADHD scores compared with placebo (24 vs 22 vs 30; P<.05). They did not report the number of subjects who had a 30% reduction in symptoms. Of note: at the end of the study but prior to unblinding, subjects were asked which medication they preferred. Twelve subjects chose dextroamphetamine, 4 chose guanfacine, and 1 chose placebo. Subjects’ stated reason for choosing dextroamphetamine was the positive effect it had on their motivation.

Another study included in this review was a randomized controlled trial of mixed amphetamine salts. Of the 27 adults who completed the study, 19 (70%) responded favorably to mixed amphetamine salts compared with 2 (7.4%) receiving placebo (NNT=1.6; P<.001).⁶ Favorable response was defined as more than a 30% reduction of symptoms on the ADHD Rating Scale. Not included in either review was a 7-week randomized controlled trial comparing methylphenidate with sustained-release buproprion.⁷ Thirty out of 37 subjects completed at least 1 week of the study. The primary indicator of a favorable response was the Clinical Global Impression Scale. The rate of response was 50% for methylphenidate, 64% for sustained-release buproprion, and 27% for placebo (P<.14).

Recommendations from others

The American Academy of Child and Adolescent Psychiatry⁸ concluded that stimulant medication can be used to treat adults who have been carefully evaluated. They recommend starting methylphenidate, dextroamphetamine, or mixed amphetamine salts according to patient and clinician preference (Table). They do not recommend the use of pemoline due to the potential for hepatic failure.

TABLE
Stimulants used to treat ADHD in adults

Evidence summary

A well-done systematic review of 12 trials assessing the efficacy of stimulant therapy in the treatment of adult ADHD did not find sufficient evidence that stimulants were effective.¹ Significant heterogeneity and poor reporting of methodology was seen among the studies.

The 1 study rated as high-quality was a 7-week randomized controlled trial using a crossover comparison of methylphenidate and placebo.² There was a favorable response in 78% (18/23) of subjects while takin methylphenidate, in contrast to 4% (1/23) while taking placebo (number needed to treat [NNT]=1.4; P<.0001). A favorable response was assessed by the Clinical Global Impression Scale, a measure of illness severity and improvement, and a >30% reduction in symptoms as measured by the ADHD Rating Scale. A more recent, but less rigorous, systematic review identified 15 studies of stimulant efficacy in adults.³ Researchers concluded that under controlled conditions, stimulants are efficacious in the treatment of ADHD in adults. The rate of response among the studies ranged from 25% to 78%.

One of the better studies in this review was a randomized, double-blind, 3-phase crossover study of dextroamphetamine, modafinil (a drug used to treat narcolepsy), and placebo.⁴ Each phase was 2 weeks long, with a 4-day washout in between. A favorable response was defined as a reduction of ADHD symptoms by at least 30% on the DSM-IV ADHD Behavior Checklist for Adults. Dextroamphetamine and modafinil showed the same response rate in 10 of 21 patients. Both treatments had a significant improvement over placebo (P<.001). It was unclear from the study what percentage of subjects responded to placebo.

A similar study compared dextroamphetamine, guanfacine (an antihypertensive agent), and placebo in 17 patients.⁵ On the DSM-IV ADHD Behavior Checklist for Adults, subjects taking dextroamphetamine or guanfacine reported similar decreases in mean ADHD scores compared with placebo (24 vs 22 vs 30; P<.05). They did not report the number of subjects who had a 30% reduction in symptoms. Of note: at the end of the study but prior to unblinding, subjects were asked which medication they preferred. Twelve subjects chose dextroamphetamine, 4 chose guanfacine, and 1 chose placebo. Subjects’ stated reason for choosing dextroamphetamine was the positive effect it had on their motivation.

Another study included in this review was a randomized controlled trial of mixed amphetamine salts. Of the 27 adults who completed the study, 19 (70%) responded favorably to mixed amphetamine salts compared with 2 (7.4%) receiving placebo (NNT=1.6; P<.001).⁶ Favorable response was defined as more than a 30% reduction of symptoms on the ADHD Rating Scale. Not included in either review was a 7-week randomized controlled trial comparing methylphenidate with sustained-release buproprion.⁷ Thirty out of 37 subjects completed at least 1 week of the study. The primary indicator of a favorable response was the Clinical Global Impression Scale. The rate of response was 50% for methylphenidate, 64% for sustained-release buproprion, and 27% for placebo (P<.14).

Recommendations from others

The American Academy of Child and Adolescent Psychiatry⁸ concluded that stimulant medication can be used to treat adults who have been carefully evaluated. They recommend starting methylphenidate, dextroamphetamine, or mixed amphetamine salts according to patient and clinician preference (Table). They do not recommend the use of pemoline due to the potential for hepatic failure.

TABLE
Stimulants used to treat ADHD in adults