Clinical Inquiries

Evidence summary

Obesity rates in the US have risen significantly in recent years: 30% of US adults (60 million people) and 16% of children 6 to 19 years old (more than 9 million), are obese,¹ and trends suggest rates will continue to increase. Eating behaviors are learned and reinforced within families, peer groups, and other important social groups. Behavioral techniques to treat obesity attempt to reduce reinforcement for unhealthy eating behaviors and teach and reinforce healthy eating behaviors. Cue avoidance is a common behavioral intervention: the patient avoids situations in which he has overeaten in the past, such as “all-you-can-eat” buffets. Role play to practice restraint from overeating, or to resist social pressure to eat at an open buffet, uses cognitive therapy as a behavioral technique. Involving family members in an obesity treatment plan and using group therapy such as Overeaters Anonymous are other standard behavioral techniques.

A 1997 systematic review of 99 weight loss studies, including randomized and nonrandomized controlled trials of at least 1 year’s duration, found 21 behavioral intervention trials that included dietary, exercise, and behavioral approaches.² The reviewers concluded that long-term behavioral techniques, dietary changes with very specific instructions to assist adherence, exercise, relapse prevention training, and social/community support were optimal for promoting weight loss.²

One of the RCTs³ involved 163 patients and compared behavioral therapy alone with behavioral therapy plus specific aids to changing diet: use of grocery lists, meal plans, and specific instructions to reduce total fat intake. The average weight loss after 1 year in the behavioral therapy with specific aids group, was statistically significantly greater than the weight loss in the behavioral therapy alone group (6.9 kg vs 3.3 kg).³

Another RCT⁴ in the review evaluated different types of maintenance programs to promote ongoing weight loss among 125 people randomized to 1 of 5 maintenance programs after an initial 20-week behavioral weight loss program: 1) control—no further contact with the behavioral therapists; 2) behavioral—ongoing problem-solving behavioral therapy sessions; 3) social—peer support and participant presentations, with some financial incentives; 4) exercise—therapy sessions, as in group 2, plus an aerobic exercise program; and 5) combined—using therapy sessions, social support and an exercise program. Mean weight loss at 1.8 months for the 4 intervention programs was significantly greater than for the control (group 2, 11.4 kg; group 3, 8.4 kg; group 4, 9.1 kg; group 5, 13.5 kg vs 3.6 kg).⁴ Two additional similar RCTs^5,6 showed significant benefit from behavioral interventions combined with social support and relapse prevention training.

One RCT⁷ addressed both behavioral therapy and the importance of face-to-face interaction. The study randomized 122 subjects to either Internet video sessions biweekly with a therapist (which included behavioral therapy, access to an associated chat room and e-mail correspondence), or to biweekly face-to-face sessions with a therapist. The active intervention spanned 24 weeks, but the therapist met with the face-to-face group and interacted in the chat room and with e-mail for another 6 months. At 18 months, the mean weight loss in the Internet group was 5.7 kg compared with 10.4 kg in the face-to-face group.⁷ In a subsequent data analysis,⁴ regular attendance to follow-up group sessions for at least 1 year resulted in better maintenance of weight loss. Initial weight loss—ie, weight loss in the first few months of the behavioral intervention—was a good predictor of long-term adherence to behavioral interventions.⁸

Hypnosis has been used as an adjunct to behavioral therapy for weight loss in multiple small studies. Two meta-analyses^9,10 concluded that behavioral therapy alone yielded an average weight loss of 6.05 kg; with the addition of hypnosis, the average weight loss rose to 14.88 kg.

Depression and binge-eating disorder commonly coexist with obesity. Obese patients seeking treatment have a lifetime prevalence of affective disorders over 30%. Depression is associated with higher dropout rates from treatment programs for obesity.¹¹ However, there are no rigorous studies that indicate that treatment of depression is necessary to achieve optimal weight loss.^12,13

Recommendations from others

The Centers for Disease Control and Prevention recommends behavior changes, including an increase in physical activity and in the intake of vegetables and fruits.¹ The American Academy of Family Physicians recommends working to improve self-efficacy—the patient’s belief that they can succeed in the intervention.¹⁴

The US Preventive Services Task Force found insufficient evidence to recommend brief counseling for obese adults, nor any counseling for overweight adults. However, they did recommend high-intensity counseling for dietary change and exercise to obese adults; this counseling is likely to produce modest sustained weight loss.¹⁵

Evidence summary

Obesity rates in the US have risen significantly in recent years: 30% of US adults (60 million people) and 16% of children 6 to 19 years old (more than 9 million), are obese,¹ and trends suggest rates will continue to increase. Eating behaviors are learned and reinforced within families, peer groups, and other important social groups. Behavioral techniques to treat obesity attempt to reduce reinforcement for unhealthy eating behaviors and teach and reinforce healthy eating behaviors. Cue avoidance is a common behavioral intervention: the patient avoids situations in which he has overeaten in the past, such as “all-you-can-eat” buffets. Role play to practice restraint from overeating, or to resist social pressure to eat at an open buffet, uses cognitive therapy as a behavioral technique. Involving family members in an obesity treatment plan and using group therapy such as Overeaters Anonymous are other standard behavioral techniques.

A 1997 systematic review of 99 weight loss studies, including randomized and nonrandomized controlled trials of at least 1 year’s duration, found 21 behavioral intervention trials that included dietary, exercise, and behavioral approaches.² The reviewers concluded that long-term behavioral techniques, dietary changes with very specific instructions to assist adherence, exercise, relapse prevention training, and social/community support were optimal for promoting weight loss.²

One of the RCTs³ involved 163 patients and compared behavioral therapy alone with behavioral therapy plus specific aids to changing diet: use of grocery lists, meal plans, and specific instructions to reduce total fat intake. The average weight loss after 1 year in the behavioral therapy with specific aids group, was statistically significantly greater than the weight loss in the behavioral therapy alone group (6.9 kg vs 3.3 kg).³

Another RCT⁴ in the review evaluated different types of maintenance programs to promote ongoing weight loss among 125 people randomized to 1 of 5 maintenance programs after an initial 20-week behavioral weight loss program: 1) control—no further contact with the behavioral therapists; 2) behavioral—ongoing problem-solving behavioral therapy sessions; 3) social—peer support and participant presentations, with some financial incentives; 4) exercise—therapy sessions, as in group 2, plus an aerobic exercise program; and 5) combined—using therapy sessions, social support and an exercise program. Mean weight loss at 1.8 months for the 4 intervention programs was significantly greater than for the control (group 2, 11.4 kg; group 3, 8.4 kg; group 4, 9.1 kg; group 5, 13.5 kg vs 3.6 kg).⁴ Two additional similar RCTs^5,6 showed significant benefit from behavioral interventions combined with social support and relapse prevention training.

One RCT⁷ addressed both behavioral therapy and the importance of face-to-face interaction. The study randomized 122 subjects to either Internet video sessions biweekly with a therapist (which included behavioral therapy, access to an associated chat room and e-mail correspondence), or to biweekly face-to-face sessions with a therapist. The active intervention spanned 24 weeks, but the therapist met with the face-to-face group and interacted in the chat room and with e-mail for another 6 months. At 18 months, the mean weight loss in the Internet group was 5.7 kg compared with 10.4 kg in the face-to-face group.⁷ In a subsequent data analysis,⁴ regular attendance to follow-up group sessions for at least 1 year resulted in better maintenance of weight loss. Initial weight loss—ie, weight loss in the first few months of the behavioral intervention—was a good predictor of long-term adherence to behavioral interventions.⁸

Hypnosis has been used as an adjunct to behavioral therapy for weight loss in multiple small studies. Two meta-analyses^9,10 concluded that behavioral therapy alone yielded an average weight loss of 6.05 kg; with the addition of hypnosis, the average weight loss rose to 14.88 kg.

Depression and binge-eating disorder commonly coexist with obesity. Obese patients seeking treatment have a lifetime prevalence of affective disorders over 30%. Depression is associated with higher dropout rates from treatment programs for obesity.¹¹ However, there are no rigorous studies that indicate that treatment of depression is necessary to achieve optimal weight loss.^12,13

Recommendations from others

The Centers for Disease Control and Prevention recommends behavior changes, including an increase in physical activity and in the intake of vegetables and fruits.¹ The American Academy of Family Physicians recommends working to improve self-efficacy—the patient’s belief that they can succeed in the intervention.¹⁴

The US Preventive Services Task Force found insufficient evidence to recommend brief counseling for obese adults, nor any counseling for overweight adults. However, they did recommend high-intensity counseling for dietary change and exercise to obese adults; this counseling is likely to produce modest sustained weight loss.¹⁵

Evidence summary

Obesity rates in the US have risen significantly in recent years: 30% of US adults (60 million people) and 16% of children 6 to 19 years old (more than 9 million), are obese,¹ and trends suggest rates will continue to increase. Eating behaviors are learned and reinforced within families, peer groups, and other important social groups. Behavioral techniques to treat obesity attempt to reduce reinforcement for unhealthy eating behaviors and teach and reinforce healthy eating behaviors. Cue avoidance is a common behavioral intervention: the patient avoids situations in which he has overeaten in the past, such as “all-you-can-eat” buffets. Role play to practice restraint from overeating, or to resist social pressure to eat at an open buffet, uses cognitive therapy as a behavioral technique. Involving family members in an obesity treatment plan and using group therapy such as Overeaters Anonymous are other standard behavioral techniques.

A 1997 systematic review of 99 weight loss studies, including randomized and nonrandomized controlled trials of at least 1 year’s duration, found 21 behavioral intervention trials that included dietary, exercise, and behavioral approaches.² The reviewers concluded that long-term behavioral techniques, dietary changes with very specific instructions to assist adherence, exercise, relapse prevention training, and social/community support were optimal for promoting weight loss.²

One of the RCTs³ involved 163 patients and compared behavioral therapy alone with behavioral therapy plus specific aids to changing diet: use of grocery lists, meal plans, and specific instructions to reduce total fat intake. The average weight loss after 1 year in the behavioral therapy with specific aids group, was statistically significantly greater than the weight loss in the behavioral therapy alone group (6.9 kg vs 3.3 kg).³

Another RCT⁴ in the review evaluated different types of maintenance programs to promote ongoing weight loss among 125 people randomized to 1 of 5 maintenance programs after an initial 20-week behavioral weight loss program: 1) control—no further contact with the behavioral therapists; 2) behavioral—ongoing problem-solving behavioral therapy sessions; 3) social—peer support and participant presentations, with some financial incentives; 4) exercise—therapy sessions, as in group 2, plus an aerobic exercise program; and 5) combined—using therapy sessions, social support and an exercise program. Mean weight loss at 1.8 months for the 4 intervention programs was significantly greater than for the control (group 2, 11.4 kg; group 3, 8.4 kg; group 4, 9.1 kg; group 5, 13.5 kg vs 3.6 kg).⁴ Two additional similar RCTs^5,6 showed significant benefit from behavioral interventions combined with social support and relapse prevention training.

One RCT⁷ addressed both behavioral therapy and the importance of face-to-face interaction. The study randomized 122 subjects to either Internet video sessions biweekly with a therapist (which included behavioral therapy, access to an associated chat room and e-mail correspondence), or to biweekly face-to-face sessions with a therapist. The active intervention spanned 24 weeks, but the therapist met with the face-to-face group and interacted in the chat room and with e-mail for another 6 months. At 18 months, the mean weight loss in the Internet group was 5.7 kg compared with 10.4 kg in the face-to-face group.⁷ In a subsequent data analysis,⁴ regular attendance to follow-up group sessions for at least 1 year resulted in better maintenance of weight loss. Initial weight loss—ie, weight loss in the first few months of the behavioral intervention—was a good predictor of long-term adherence to behavioral interventions.⁸

Hypnosis has been used as an adjunct to behavioral therapy for weight loss in multiple small studies. Two meta-analyses^9,10 concluded that behavioral therapy alone yielded an average weight loss of 6.05 kg; with the addition of hypnosis, the average weight loss rose to 14.88 kg.

Depression and binge-eating disorder commonly coexist with obesity. Obese patients seeking treatment have a lifetime prevalence of affective disorders over 30%. Depression is associated with higher dropout rates from treatment programs for obesity.¹¹ However, there are no rigorous studies that indicate that treatment of depression is necessary to achieve optimal weight loss.^12,13

Recommendations from others

The Centers for Disease Control and Prevention recommends behavior changes, including an increase in physical activity and in the intake of vegetables and fruits.¹ The American Academy of Family Physicians recommends working to improve self-efficacy—the patient’s belief that they can succeed in the intervention.¹⁴

The US Preventive Services Task Force found insufficient evidence to recommend brief counseling for obese adults, nor any counseling for overweight adults. However, they did recommend high-intensity counseling for dietary change and exercise to obese adults; this counseling is likely to produce modest sustained weight loss.¹⁵

Evidence summary

The benefits of statin therapy appear to extend beyond the realm of their cholesterol-lowering properties.⁴ These benefits, such as reduction in post—myocardial infarction (MI) deaths and reinfarctions, are seen quickly after initiation of therapy. Other drugs, such as aspirin and beta-blockers, have also been shown to improve early outcomes when started after cardiovascular events, although waiting until the patient is hemodynamically stable to initiate beta-blockade reduces the risk of cardiogenic shock.⁵ If standard agents are either not started or withdrawn after a cardiovascular event, patients are at increased risk of harm.^6,7

Physiological research. Studies of patients with stroke and those with only risk factors for cardiovascular disease show that platelet activity is increased when statins are discontinued.^8,9 Additionally, tissue plasminogen activator levels are decreased after discontinuation of statins, resulting in a relatively hypercoagulable state.¹⁰ Animal studies of stroke in mice showed mice whose statin was abruptly stopped had more damage from stroke than those whose statin was continued.¹¹

High-risk cardiovascular patients. Preliminary human data suggested that stopping statins increased risk of recurrent events for patients who recently had a primary cardiovascular event. One retrospective case-control study evaluated 4870 patients who had statin therapy withdrawn on admission to the hospital for non-ST segment elevation MI (NSTEMI). Patients who had their statins withheld had increased rates of heart failure, arrhythmia, shock, and death (hazard ratio=2.32; 95% confidence interval [CI], 2.02–2.67).¹² A post-hoc analysis of data from the PRISM trial found that among the 86 patients who were admitted for chest pain and had their statin withdrawn, a higher rate of death and nonfatal MI was observed, compared with the 379 patients whose statins were continued (hazard ratio=2.93; 95% CI, 1.64–6.27). This effect was seen in the first week and was independent of cholesterol levels and measures of severity of illness.¹³

Low-risk cardiovascular patients. A post-hoc analysis of the washout period of a prospective study of 9473 asymptomatic outpatients who were previously taking statins showed that for these lower-risk patients, similar rates of cardiovascular events could be expected during withdrawal (any statin) or initiation of atorvastatin therapy. The monthly event rate during the discontinuation phase was 0.20% and during initiation was 0.26% (P=NS).¹⁴

Recommendations from others

Currently, no expert panels or specialty bodies make recommendations regarding how or when to discontinue statins. The Institute for Clinical Systems Improvement recommends that all patients with chronic stable coronary artery disease should be considered for statin use regardless of their lipid levels; however, no mention of discontinuing statins is made.¹⁵

Evidence summary

The benefits of statin therapy appear to extend beyond the realm of their cholesterol-lowering properties.⁴ These benefits, such as reduction in post—myocardial infarction (MI) deaths and reinfarctions, are seen quickly after initiation of therapy. Other drugs, such as aspirin and beta-blockers, have also been shown to improve early outcomes when started after cardiovascular events, although waiting until the patient is hemodynamically stable to initiate beta-blockade reduces the risk of cardiogenic shock.⁵ If standard agents are either not started or withdrawn after a cardiovascular event, patients are at increased risk of harm.^6,7

Physiological research. Studies of patients with stroke and those with only risk factors for cardiovascular disease show that platelet activity is increased when statins are discontinued.^8,9 Additionally, tissue plasminogen activator levels are decreased after discontinuation of statins, resulting in a relatively hypercoagulable state.¹⁰ Animal studies of stroke in mice showed mice whose statin was abruptly stopped had more damage from stroke than those whose statin was continued.¹¹

High-risk cardiovascular patients. Preliminary human data suggested that stopping statins increased risk of recurrent events for patients who recently had a primary cardiovascular event. One retrospective case-control study evaluated 4870 patients who had statin therapy withdrawn on admission to the hospital for non-ST segment elevation MI (NSTEMI). Patients who had their statins withheld had increased rates of heart failure, arrhythmia, shock, and death (hazard ratio=2.32; 95% confidence interval [CI], 2.02–2.67).¹² A post-hoc analysis of data from the PRISM trial found that among the 86 patients who were admitted for chest pain and had their statin withdrawn, a higher rate of death and nonfatal MI was observed, compared with the 379 patients whose statins were continued (hazard ratio=2.93; 95% CI, 1.64–6.27). This effect was seen in the first week and was independent of cholesterol levels and measures of severity of illness.¹³

Low-risk cardiovascular patients. A post-hoc analysis of the washout period of a prospective study of 9473 asymptomatic outpatients who were previously taking statins showed that for these lower-risk patients, similar rates of cardiovascular events could be expected during withdrawal (any statin) or initiation of atorvastatin therapy. The monthly event rate during the discontinuation phase was 0.20% and during initiation was 0.26% (P=NS).¹⁴

Recommendations from others

Currently, no expert panels or specialty bodies make recommendations regarding how or when to discontinue statins. The Institute for Clinical Systems Improvement recommends that all patients with chronic stable coronary artery disease should be considered for statin use regardless of their lipid levels; however, no mention of discontinuing statins is made.¹⁵

Evidence summary

The benefits of statin therapy appear to extend beyond the realm of their cholesterol-lowering properties.⁴ These benefits, such as reduction in post—myocardial infarction (MI) deaths and reinfarctions, are seen quickly after initiation of therapy. Other drugs, such as aspirin and beta-blockers, have also been shown to improve early outcomes when started after cardiovascular events, although waiting until the patient is hemodynamically stable to initiate beta-blockade reduces the risk of cardiogenic shock.⁵ If standard agents are either not started or withdrawn after a cardiovascular event, patients are at increased risk of harm.^6,7

Physiological research. Studies of patients with stroke and those with only risk factors for cardiovascular disease show that platelet activity is increased when statins are discontinued.^8,9 Additionally, tissue plasminogen activator levels are decreased after discontinuation of statins, resulting in a relatively hypercoagulable state.¹⁰ Animal studies of stroke in mice showed mice whose statin was abruptly stopped had more damage from stroke than those whose statin was continued.¹¹

High-risk cardiovascular patients. Preliminary human data suggested that stopping statins increased risk of recurrent events for patients who recently had a primary cardiovascular event. One retrospective case-control study evaluated 4870 patients who had statin therapy withdrawn on admission to the hospital for non-ST segment elevation MI (NSTEMI). Patients who had their statins withheld had increased rates of heart failure, arrhythmia, shock, and death (hazard ratio=2.32; 95% confidence interval [CI], 2.02–2.67).¹² A post-hoc analysis of data from the PRISM trial found that among the 86 patients who were admitted for chest pain and had their statin withdrawn, a higher rate of death and nonfatal MI was observed, compared with the 379 patients whose statins were continued (hazard ratio=2.93; 95% CI, 1.64–6.27). This effect was seen in the first week and was independent of cholesterol levels and measures of severity of illness.¹³

Low-risk cardiovascular patients. A post-hoc analysis of the washout period of a prospective study of 9473 asymptomatic outpatients who were previously taking statins showed that for these lower-risk patients, similar rates of cardiovascular events could be expected during withdrawal (any statin) or initiation of atorvastatin therapy. The monthly event rate during the discontinuation phase was 0.20% and during initiation was 0.26% (P=NS).¹⁴

Recommendations from others

Currently, no expert panels or specialty bodies make recommendations regarding how or when to discontinue statins. The Institute for Clinical Systems Improvement recommends that all patients with chronic stable coronary artery disease should be considered for statin use regardless of their lipid levels; however, no mention of discontinuing statins is made.¹⁵

Evidence summary

The prevalence of migraine headache is 6% among men and 15% to 17% among women.¹ However, no standardized approach exists for the treatment of acute migraine headache. Systematic reviews of randomized controlled trials (RCTs) summarized that oral sumatriptan (Imitrex), eletriptan (Relpax), and rizatriptan (Maxalt) reduced migraine headache pain and increased the pain-free response rate for adults when compared with placebo.^2-4 The number needed to treat (NNT) ranged from 3.9 to 9.9 for a given triptan’s lower dose to 2.6 to 5.1 for the higher dose.^2-4 RCTs reported superior efficacy of oral almotriptan (Axert), frovatriptan (Frova), and zolmitriptan (Zomig), as well as intranasal sumatriptan and zolmitriptan when compared with placebo.

The following NSAIDs reduced headache severity more than placebo 2 hours after treatment: aspirin (1000 mg; NNT=2.4), ibuprofen (1200 mg; NNT=1.8), naproxen (750 mg; NNT=2.0), tolfenamic acid (not available in the US; NNT=1.2), and the combination product of acetaminophen/aspirin/caffeine (Excedrin Migraine, et al) (NNT=1.7).⁵ Acetaminophen 1000 mg orally has been reported to be superior to placebo for treating pain, functional disability, and photo/phonophobia among patients who did not require bedrest with their headaches and did not vomit more than 20% of the time. However, it was not superior to placebo when given intravenously for more severe acute migraine. No placebo-controlled trials exist for the use of ketorolac (Toradol); there are only comparison studies against other active migraine medications. Ketoprofen (Orudis) has placebo-controlled RCT data supporting its efficacy.

A meta-analysis⁶ of RCTs of parenteral metoclopramide (Reglan) revealed significant pain reduction (odds ratio [OR]=2.84; 95% confidence interval [CI], 1.05–7.68). When compared with other antiemetics (chlorpromazine [Thorazine] and prochlorperazine [Compazine]), metoclopramide was either less effective (OR=0.39; 95% CI, 0.18–0.87) or no different (OR=0.64; 95% CI, 0.23–1.76) than other therapies for reducing migraine pain. No difference was noted between parenteral metoclopramide and subcutaneous sumatriptan (OR=2.27; 95% CI, 0.64–8.11); however, metoclopramide was more effective than ibuprofen in pain reduction scores (standard deviation data missing in this study).

A systematic review⁷ revealed that dihydroergotamine (DHE) alone was less effective than subcutaneous sumatriptan in migraine pain reduction (OR=0.44; 95% CI, 0.25–0.77) or headache resolution (OR=0.05; 95% CI, 0.01–0.42). No differences were seen between DHE alone and chlorpromazine or lidocaine. Three studies revealed DHE plus metoclopramide was more effective than or equal to other agents for headache pain reduction at 2 hours: one vs ketorolac IM (OR=7; 95% CI, 0.86–56.89), one vs meperidine (Demerol) plus hydroxyzine (Vistaril, Atarax) IM (OR=47.67; 95% CI, 4.32–526.17), and one vs valproate IV (OR=0.67; 95% CI, 0.19–2.33).⁷ Specifically, treatment with DHE plus metoclopramide was superior to ketorolac for pain reduction (P=.03), but patients did not differ in disability scores (P=.06). DHE plus metoclopramide achieved greater reductions in pain scale scores than meperidine plus hydroxyzine (P<.001). No significant difference in pain reduction was noted between DHE plus metoclopramide and valproate (P=.36).

A multicenter, double-blind, randomized parallel group study⁸ showed no difference between the combination product isometheptene mucate, dichloralphenazone with acetaminophen (Midrin, Duradrin, etc) (used as recommended in the package insert with a maximum of up to 5 tablets within 24 hours) vs oral sumatriptan (initial dose of 25 mg with a repeat 25 mg dose in 2 hours). No placebo arm was used in this study.

Recommendations from others

The Institute for Clinical Systems Improvement recommends the use of vasoactive drugs over narcotics and barbiturates for treatment of moderately severe migraine headaches.⁹ The American Academy of Neurology recommends migraine-specific medications (triptans, DHE) for moderate to severe migraines or those mild to moderate migraines that responded poorly to NSAIDs or other over-the-counter preparations.¹⁰

Evidence summary

The prevalence of migraine headache is 6% among men and 15% to 17% among women.¹ However, no standardized approach exists for the treatment of acute migraine headache. Systematic reviews of randomized controlled trials (RCTs) summarized that oral sumatriptan (Imitrex), eletriptan (Relpax), and rizatriptan (Maxalt) reduced migraine headache pain and increased the pain-free response rate for adults when compared with placebo.^2-4 The number needed to treat (NNT) ranged from 3.9 to 9.9 for a given triptan’s lower dose to 2.6 to 5.1 for the higher dose.^2-4 RCTs reported superior efficacy of oral almotriptan (Axert), frovatriptan (Frova), and zolmitriptan (Zomig), as well as intranasal sumatriptan and zolmitriptan when compared with placebo.

The following NSAIDs reduced headache severity more than placebo 2 hours after treatment: aspirin (1000 mg; NNT=2.4), ibuprofen (1200 mg; NNT=1.8), naproxen (750 mg; NNT=2.0), tolfenamic acid (not available in the US; NNT=1.2), and the combination product of acetaminophen/aspirin/caffeine (Excedrin Migraine, et al) (NNT=1.7).⁵ Acetaminophen 1000 mg orally has been reported to be superior to placebo for treating pain, functional disability, and photo/phonophobia among patients who did not require bedrest with their headaches and did not vomit more than 20% of the time. However, it was not superior to placebo when given intravenously for more severe acute migraine. No placebo-controlled trials exist for the use of ketorolac (Toradol); there are only comparison studies against other active migraine medications. Ketoprofen (Orudis) has placebo-controlled RCT data supporting its efficacy.

A meta-analysis⁶ of RCTs of parenteral metoclopramide (Reglan) revealed significant pain reduction (odds ratio [OR]=2.84; 95% confidence interval [CI], 1.05–7.68). When compared with other antiemetics (chlorpromazine [Thorazine] and prochlorperazine [Compazine]), metoclopramide was either less effective (OR=0.39; 95% CI, 0.18–0.87) or no different (OR=0.64; 95% CI, 0.23–1.76) than other therapies for reducing migraine pain. No difference was noted between parenteral metoclopramide and subcutaneous sumatriptan (OR=2.27; 95% CI, 0.64–8.11); however, metoclopramide was more effective than ibuprofen in pain reduction scores (standard deviation data missing in this study).

A systematic review⁷ revealed that dihydroergotamine (DHE) alone was less effective than subcutaneous sumatriptan in migraine pain reduction (OR=0.44; 95% CI, 0.25–0.77) or headache resolution (OR=0.05; 95% CI, 0.01–0.42). No differences were seen between DHE alone and chlorpromazine or lidocaine. Three studies revealed DHE plus metoclopramide was more effective than or equal to other agents for headache pain reduction at 2 hours: one vs ketorolac IM (OR=7; 95% CI, 0.86–56.89), one vs meperidine (Demerol) plus hydroxyzine (Vistaril, Atarax) IM (OR=47.67; 95% CI, 4.32–526.17), and one vs valproate IV (OR=0.67; 95% CI, 0.19–2.33).⁷ Specifically, treatment with DHE plus metoclopramide was superior to ketorolac for pain reduction (P=.03), but patients did not differ in disability scores (P=.06). DHE plus metoclopramide achieved greater reductions in pain scale scores than meperidine plus hydroxyzine (P<.001). No significant difference in pain reduction was noted between DHE plus metoclopramide and valproate (P=.36).

A multicenter, double-blind, randomized parallel group study⁸ showed no difference between the combination product isometheptene mucate, dichloralphenazone with acetaminophen (Midrin, Duradrin, etc) (used as recommended in the package insert with a maximum of up to 5 tablets within 24 hours) vs oral sumatriptan (initial dose of 25 mg with a repeat 25 mg dose in 2 hours). No placebo arm was used in this study.

Recommendations from others

The Institute for Clinical Systems Improvement recommends the use of vasoactive drugs over narcotics and barbiturates for treatment of moderately severe migraine headaches.⁹ The American Academy of Neurology recommends migraine-specific medications (triptans, DHE) for moderate to severe migraines or those mild to moderate migraines that responded poorly to NSAIDs or other over-the-counter preparations.¹⁰

Evidence summary

The prevalence of migraine headache is 6% among men and 15% to 17% among women.¹ However, no standardized approach exists for the treatment of acute migraine headache. Systematic reviews of randomized controlled trials (RCTs) summarized that oral sumatriptan (Imitrex), eletriptan (Relpax), and rizatriptan (Maxalt) reduced migraine headache pain and increased the pain-free response rate for adults when compared with placebo.^2-4 The number needed to treat (NNT) ranged from 3.9 to 9.9 for a given triptan’s lower dose to 2.6 to 5.1 for the higher dose.^2-4 RCTs reported superior efficacy of oral almotriptan (Axert), frovatriptan (Frova), and zolmitriptan (Zomig), as well as intranasal sumatriptan and zolmitriptan when compared with placebo.

The following NSAIDs reduced headache severity more than placebo 2 hours after treatment: aspirin (1000 mg; NNT=2.4), ibuprofen (1200 mg; NNT=1.8), naproxen (750 mg; NNT=2.0), tolfenamic acid (not available in the US; NNT=1.2), and the combination product of acetaminophen/aspirin/caffeine (Excedrin Migraine, et al) (NNT=1.7).⁵ Acetaminophen 1000 mg orally has been reported to be superior to placebo for treating pain, functional disability, and photo/phonophobia among patients who did not require bedrest with their headaches and did not vomit more than 20% of the time. However, it was not superior to placebo when given intravenously for more severe acute migraine. No placebo-controlled trials exist for the use of ketorolac (Toradol); there are only comparison studies against other active migraine medications. Ketoprofen (Orudis) has placebo-controlled RCT data supporting its efficacy.

A meta-analysis⁶ of RCTs of parenteral metoclopramide (Reglan) revealed significant pain reduction (odds ratio [OR]=2.84; 95% confidence interval [CI], 1.05–7.68). When compared with other antiemetics (chlorpromazine [Thorazine] and prochlorperazine [Compazine]), metoclopramide was either less effective (OR=0.39; 95% CI, 0.18–0.87) or no different (OR=0.64; 95% CI, 0.23–1.76) than other therapies for reducing migraine pain. No difference was noted between parenteral metoclopramide and subcutaneous sumatriptan (OR=2.27; 95% CI, 0.64–8.11); however, metoclopramide was more effective than ibuprofen in pain reduction scores (standard deviation data missing in this study).

A systematic review⁷ revealed that dihydroergotamine (DHE) alone was less effective than subcutaneous sumatriptan in migraine pain reduction (OR=0.44; 95% CI, 0.25–0.77) or headache resolution (OR=0.05; 95% CI, 0.01–0.42). No differences were seen between DHE alone and chlorpromazine or lidocaine. Three studies revealed DHE plus metoclopramide was more effective than or equal to other agents for headache pain reduction at 2 hours: one vs ketorolac IM (OR=7; 95% CI, 0.86–56.89), one vs meperidine (Demerol) plus hydroxyzine (Vistaril, Atarax) IM (OR=47.67; 95% CI, 4.32–526.17), and one vs valproate IV (OR=0.67; 95% CI, 0.19–2.33).⁷ Specifically, treatment with DHE plus metoclopramide was superior to ketorolac for pain reduction (P=.03), but patients did not differ in disability scores (P=.06). DHE plus metoclopramide achieved greater reductions in pain scale scores than meperidine plus hydroxyzine (P<.001). No significant difference in pain reduction was noted between DHE plus metoclopramide and valproate (P=.36).

A multicenter, double-blind, randomized parallel group study⁸ showed no difference between the combination product isometheptene mucate, dichloralphenazone with acetaminophen (Midrin, Duradrin, etc) (used as recommended in the package insert with a maximum of up to 5 tablets within 24 hours) vs oral sumatriptan (initial dose of 25 mg with a repeat 25 mg dose in 2 hours). No placebo arm was used in this study.

Recommendations from others

The Institute for Clinical Systems Improvement recommends the use of vasoactive drugs over narcotics and barbiturates for treatment of moderately severe migraine headaches.⁹ The American Academy of Neurology recommends migraine-specific medications (triptans, DHE) for moderate to severe migraines or those mild to moderate migraines that responded poorly to NSAIDs or other over-the-counter preparations.¹⁰

Evidence summary

Hospices have varying admission criteria. However, according to US law, patients must be certified to be “terminally ill” with a prognosis of less than 6 months to live in order to qualify for the Medicare hospice benefit.¹ US law and Medicare regulations specify that an attending physician and the accepting hospice medical director must agree to the prognosis for certification of eligibility.

Brickner et al’s survey² demonstrated that physicians find accurate prognostication difficult. Furthermore, many of the common noncancer diseases have erratic and unpredictable courses, making prognosis even harder. Indeed, patients with noncancer diagnoses are typically admitted to hospices later in their terminal course, ³ resulting in increased inpatient hospital stays⁴ and ultimately lower patient and family satisfaction. ⁵ The difficulties inherent in prognostication were underscored by a study that found patients with non-cancer diagnoses to be much more likely to be discharged from hospice alive.⁶

The National Hospice Organization (NHO) has created guidelines⁷ for determining prognosis in selected noncancer diseases including heart disease, pulmonary disease, dementia, HIV, liver disease, renal disease, stroke, coma, and amyotrophic lateral sclerosis (ALS). To validate these guidelines, one group identified 2607 patients who meet the NHO guidelines.⁸ Only 655 (25%) were dead within 6 months. The estimated median survival of these identified patients was 804 days. When every potential prognostic criterion was met (far more than NHO standards) only 19 of the 2607 patients qualified for hospice, and yet 10 of them were still alive at 6 months. Unlike many cancers, in which there is a steady terminal decline, diseases such as chronic obstructive pulmonary disease, congestive heart failure, and liver failure are characterized by a baseline of moderate functioning with intermittent—often life-threatening—exacerbations.

A recent Clinical Inquiry⁹ addressed the issue of hospice care for patients with late-stage Alzheimer’s disease. That evidence-based answer concluded that criteria superior to the NHO guidelines or clinical judgment had been established for prognosis of Alzheimer’s disease. However, using those improved criteria yielded only marginally more accurate prognostication. At best, 71% of the patients predicted to live less than 6 months did so, but only if the patients had progressed through the disease in an orderly fashion. For the larger subset of patients, those who did not progress through Alzheimer’s in a predictable way, only 30% of the patients actually died within 6 months.

Recommendations from others

The NHO⁷ provides parameters to help determine a 6-month life expectancy. The “General Guidelines for Determining Prognosis” are summarized in the TABLE. Further details of the “general guidelines” as well as guidelines for prognosis in specific diseases (heart disease, pulmonary disease, dementia, HIV, liver disease, renal disease, stroke, coma, and ALS) are outlined by the NHO.⁷

TABLE
Hospice criteria

Evidence summary

Hospices have varying admission criteria. However, according to US law, patients must be certified to be “terminally ill” with a prognosis of less than 6 months to live in order to qualify for the Medicare hospice benefit.¹ US law and Medicare regulations specify that an attending physician and the accepting hospice medical director must agree to the prognosis for certification of eligibility.

Brickner et al’s survey² demonstrated that physicians find accurate prognostication difficult. Furthermore, many of the common noncancer diseases have erratic and unpredictable courses, making prognosis even harder. Indeed, patients with noncancer diagnoses are typically admitted to hospices later in their terminal course, ³ resulting in increased inpatient hospital stays⁴ and ultimately lower patient and family satisfaction. ⁵ The difficulties inherent in prognostication were underscored by a study that found patients with non-cancer diagnoses to be much more likely to be discharged from hospice alive.⁶

The National Hospice Organization (NHO) has created guidelines⁷ for determining prognosis in selected noncancer diseases including heart disease, pulmonary disease, dementia, HIV, liver disease, renal disease, stroke, coma, and amyotrophic lateral sclerosis (ALS). To validate these guidelines, one group identified 2607 patients who meet the NHO guidelines.⁸ Only 655 (25%) were dead within 6 months. The estimated median survival of these identified patients was 804 days. When every potential prognostic criterion was met (far more than NHO standards) only 19 of the 2607 patients qualified for hospice, and yet 10 of them were still alive at 6 months. Unlike many cancers, in which there is a steady terminal decline, diseases such as chronic obstructive pulmonary disease, congestive heart failure, and liver failure are characterized by a baseline of moderate functioning with intermittent—often life-threatening—exacerbations.

A recent Clinical Inquiry⁹ addressed the issue of hospice care for patients with late-stage Alzheimer’s disease. That evidence-based answer concluded that criteria superior to the NHO guidelines or clinical judgment had been established for prognosis of Alzheimer’s disease. However, using those improved criteria yielded only marginally more accurate prognostication. At best, 71% of the patients predicted to live less than 6 months did so, but only if the patients had progressed through the disease in an orderly fashion. For the larger subset of patients, those who did not progress through Alzheimer’s in a predictable way, only 30% of the patients actually died within 6 months.

Recommendations from others

The NHO⁷ provides parameters to help determine a 6-month life expectancy. The “General Guidelines for Determining Prognosis” are summarized in the TABLE. Further details of the “general guidelines” as well as guidelines for prognosis in specific diseases (heart disease, pulmonary disease, dementia, HIV, liver disease, renal disease, stroke, coma, and ALS) are outlined by the NHO.⁷

TABLE
Hospice criteria

Evidence summary

Hospices have varying admission criteria. However, according to US law, patients must be certified to be “terminally ill” with a prognosis of less than 6 months to live in order to qualify for the Medicare hospice benefit.¹ US law and Medicare regulations specify that an attending physician and the accepting hospice medical director must agree to the prognosis for certification of eligibility.

Brickner et al’s survey² demonstrated that physicians find accurate prognostication difficult. Furthermore, many of the common noncancer diseases have erratic and unpredictable courses, making prognosis even harder. Indeed, patients with noncancer diagnoses are typically admitted to hospices later in their terminal course, ³ resulting in increased inpatient hospital stays⁴ and ultimately lower patient and family satisfaction. ⁵ The difficulties inherent in prognostication were underscored by a study that found patients with non-cancer diagnoses to be much more likely to be discharged from hospice alive.⁶

The National Hospice Organization (NHO) has created guidelines⁷ for determining prognosis in selected noncancer diseases including heart disease, pulmonary disease, dementia, HIV, liver disease, renal disease, stroke, coma, and amyotrophic lateral sclerosis (ALS). To validate these guidelines, one group identified 2607 patients who meet the NHO guidelines.⁸ Only 655 (25%) were dead within 6 months. The estimated median survival of these identified patients was 804 days. When every potential prognostic criterion was met (far more than NHO standards) only 19 of the 2607 patients qualified for hospice, and yet 10 of them were still alive at 6 months. Unlike many cancers, in which there is a steady terminal decline, diseases such as chronic obstructive pulmonary disease, congestive heart failure, and liver failure are characterized by a baseline of moderate functioning with intermittent—often life-threatening—exacerbations.

A recent Clinical Inquiry⁹ addressed the issue of hospice care for patients with late-stage Alzheimer’s disease. That evidence-based answer concluded that criteria superior to the NHO guidelines or clinical judgment had been established for prognosis of Alzheimer’s disease. However, using those improved criteria yielded only marginally more accurate prognostication. At best, 71% of the patients predicted to live less than 6 months did so, but only if the patients had progressed through the disease in an orderly fashion. For the larger subset of patients, those who did not progress through Alzheimer’s in a predictable way, only 30% of the patients actually died within 6 months.

Recommendations from others

The NHO⁷ provides parameters to help determine a 6-month life expectancy. The “General Guidelines for Determining Prognosis” are summarized in the TABLE. Further details of the “general guidelines” as well as guidelines for prognosis in specific diseases (heart disease, pulmonary disease, dementia, HIV, liver disease, renal disease, stroke, coma, and ALS) are outlined by the NHO.⁷

TABLE
Hospice criteria

Evidence summary

An effective screening test for HSV would need to identify those with HSV infection before substantial morbidity resulted, and effective interventions would need to be available for use in the asymptomatic stage. Screening for HSV-2 must also consider the psychosocial impact of serologic diagnosis in those without symptoms, as a qualitative study showed both negative and positive emotional responses in those with positive serology, with short-term emotional responses described as surprise, denial, confusion, distress, disappointment, and sense of relief.¹ Patients also expressed fear of partner notification, concern for transmission to newborns, and concern for social stigma.

Pre- and post-test counseling must accompany testing as negative emotional or psychological responses are amenable to this intervention. A consideration for screening decisions is the positive predictive value (PPV) of testing for the specific patient, which ranges from 58% (in a British population with 4% prevalence) to 90% (in a population with 22% prevalence taken from sexually transmitted disease clinics in the Netherlands).² (A PPV of 58% means that only 58% of women with a positive test actually had the disease, and 42% were false-positive).

The primary goal for screening pregnant women is prevention of neonatal transmission of HSV. A prospective observational study³ of 7046 women found that acquisition of HSV-2 during pregnancy was asymptomatic in 74% of 94 cases. No increase in neonatal or pregnancy-related morbidity was seen for those patients who had seroconverted by the time of labor. The main benefit of serology testing during pregnancy has been to identify patients with asymptomatic infection and counsel them on reporting new symptoms for evaluation and treatment.

Another prospective cohort study⁴ identified seropositive pregnant women with no history of genital herpes. Forty-three of 264 (16%) of these women were able to identify and report clinical HSV to their physician during the pregnancy.

Testing of asymptomatic patients with HSV-2 serology and counseling has been recommended by some experts⁵ for motivated patients with current or recent sexually transmitted infection or HIV infection and for partners of HSV-positive patients.⁶ Screening could give those identified the opportunity to learn to recognize symptoms, decrease transmission, and understand risks of acquiring HIV or other sexually transmitted infections. Patients screening negative might have heightened awareness to susceptibility and reinforce lifestyle changes.⁶ Success of HSV prevention strategies is reviewed elsewhere.⁷

Recommendations from others

The Centers for Disease Control and Prevention, the United States Preventive Services Task Force, and the American Academy of Family Physicians do not recommend screening asymptomatic adults for HSV infection.^7,8 The American College of Obstetricians and Gynecologists does not recommend routine screening of pregnant women for HSV.⁹

Evidence summary

An effective screening test for HSV would need to identify those with HSV infection before substantial morbidity resulted, and effective interventions would need to be available for use in the asymptomatic stage. Screening for HSV-2 must also consider the psychosocial impact of serologic diagnosis in those without symptoms, as a qualitative study showed both negative and positive emotional responses in those with positive serology, with short-term emotional responses described as surprise, denial, confusion, distress, disappointment, and sense of relief.¹ Patients also expressed fear of partner notification, concern for transmission to newborns, and concern for social stigma.

Pre- and post-test counseling must accompany testing as negative emotional or psychological responses are amenable to this intervention. A consideration for screening decisions is the positive predictive value (PPV) of testing for the specific patient, which ranges from 58% (in a British population with 4% prevalence) to 90% (in a population with 22% prevalence taken from sexually transmitted disease clinics in the Netherlands).² (A PPV of 58% means that only 58% of women with a positive test actually had the disease, and 42% were false-positive).

The primary goal for screening pregnant women is prevention of neonatal transmission of HSV. A prospective observational study³ of 7046 women found that acquisition of HSV-2 during pregnancy was asymptomatic in 74% of 94 cases. No increase in neonatal or pregnancy-related morbidity was seen for those patients who had seroconverted by the time of labor. The main benefit of serology testing during pregnancy has been to identify patients with asymptomatic infection and counsel them on reporting new symptoms for evaluation and treatment.

Another prospective cohort study⁴ identified seropositive pregnant women with no history of genital herpes. Forty-three of 264 (16%) of these women were able to identify and report clinical HSV to their physician during the pregnancy.

Testing of asymptomatic patients with HSV-2 serology and counseling has been recommended by some experts⁵ for motivated patients with current or recent sexually transmitted infection or HIV infection and for partners of HSV-positive patients.⁶ Screening could give those identified the opportunity to learn to recognize symptoms, decrease transmission, and understand risks of acquiring HIV or other sexually transmitted infections. Patients screening negative might have heightened awareness to susceptibility and reinforce lifestyle changes.⁶ Success of HSV prevention strategies is reviewed elsewhere.⁷

Recommendations from others

The Centers for Disease Control and Prevention, the United States Preventive Services Task Force, and the American Academy of Family Physicians do not recommend screening asymptomatic adults for HSV infection.^7,8 The American College of Obstetricians and Gynecologists does not recommend routine screening of pregnant women for HSV.⁹

Evidence summary

An effective screening test for HSV would need to identify those with HSV infection before substantial morbidity resulted, and effective interventions would need to be available for use in the asymptomatic stage. Screening for HSV-2 must also consider the psychosocial impact of serologic diagnosis in those without symptoms, as a qualitative study showed both negative and positive emotional responses in those with positive serology, with short-term emotional responses described as surprise, denial, confusion, distress, disappointment, and sense of relief.¹ Patients also expressed fear of partner notification, concern for transmission to newborns, and concern for social stigma.

Pre- and post-test counseling must accompany testing as negative emotional or psychological responses are amenable to this intervention. A consideration for screening decisions is the positive predictive value (PPV) of testing for the specific patient, which ranges from 58% (in a British population with 4% prevalence) to 90% (in a population with 22% prevalence taken from sexually transmitted disease clinics in the Netherlands).² (A PPV of 58% means that only 58% of women with a positive test actually had the disease, and 42% were false-positive).

The primary goal for screening pregnant women is prevention of neonatal transmission of HSV. A prospective observational study³ of 7046 women found that acquisition of HSV-2 during pregnancy was asymptomatic in 74% of 94 cases. No increase in neonatal or pregnancy-related morbidity was seen for those patients who had seroconverted by the time of labor. The main benefit of serology testing during pregnancy has been to identify patients with asymptomatic infection and counsel them on reporting new symptoms for evaluation and treatment.

Another prospective cohort study⁴ identified seropositive pregnant women with no history of genital herpes. Forty-three of 264 (16%) of these women were able to identify and report clinical HSV to their physician during the pregnancy.

Testing of asymptomatic patients with HSV-2 serology and counseling has been recommended by some experts⁵ for motivated patients with current or recent sexually transmitted infection or HIV infection and for partners of HSV-positive patients.⁶ Screening could give those identified the opportunity to learn to recognize symptoms, decrease transmission, and understand risks of acquiring HIV or other sexually transmitted infections. Patients screening negative might have heightened awareness to susceptibility and reinforce lifestyle changes.⁶ Success of HSV prevention strategies is reviewed elsewhere.⁷

Recommendations from others

The Centers for Disease Control and Prevention, the United States Preventive Services Task Force, and the American Academy of Family Physicians do not recommend screening asymptomatic adults for HSV infection.^7,8 The American College of Obstetricians and Gynecologists does not recommend routine screening of pregnant women for HSV.⁹

Evidence summary

Idiopathic toe-walking is a childhood condition of unknown cause characterized by persistence of a tiptoe gait pattern without evidence of neurologic, orthopedic, or psychiatric disease.¹ The incidence in the general population is not known. Children with idiopathic toe-walking usually have limited ankle dorsiflexion and are able to walk with a heel-strike for short periods when asked to do so. Longitudinal data is lacking to determine whether ankle equinus is the primary cause of idiopathic toe-walking or is a consequence of chronically walking on tiptoes. A family history of toe-walking ranges from 30% to 71% in the literature and is considered a characteristic of idiopathic toe walking.^2-4

Evaluation. An important element of the evaluation of idiopathic toe-walking is to distinguish it from neuromuscular disorders associated with toe-walking, such as mild cerebral palsy. Case series with small numbers of subjects (range=27–41) have used gait electromyography (EMG) to distinguish cerebral palsy from idiopathic toe-walking.^4-6 The overlap in gait EMG values in cerebral palsy and idiopathic toe-walking precludes its use as a differentiating diagnostic test.

The only aspect of EMG testing that has been useful in differentiating cerebral palsy from idiopathic toe-walking is gastrocnemius coactivation during resisted knee extension—a finding indicative of neurologic pathology.^5,6 Kinematic analysis and observation of gait and measurement of ankle range of motion have been studied as diagnostic tools to differentiate idiopathic toe-walking from cerebral palsy.^5-8 In the largest of these 4 studies (23 children with mild cerebral palsy and 22 with idiopathic toe-walking), maximal knee extension occurred at ground contact in the idiopathic toe-walking group whereas in the mild cerebral palsy group, the knee was flexed at ground contact.⁷ Measurement of ankle range of motion is not reliable in distinguishing between idiopathic toe-walking and cerebral palsy groups.^5-7

Treatment. Simple observation, physical therapy, serial casting, and Achilles tendon lengthening surgery have been studied in the treatment of idiopathic toe-walking.^2,3,9-11 In the largest case series (n=136),¹⁰ the frequency of toe-walking decreased in 51% of those in both the observation and casted groups. In this same study, the surgical group had lower rates of toe-walking, but no direct comparisons could be made to the nonsurgical groups because the patients in the surgical group were older and had longer follow-up than the other groups.

In a retrospective comparison³ of observation (which included physical therapy and special shoes), casting, and surgery among 80 children with idiopathic toe-walking, surgery resulted in significantly higher parental satisfaction (satisfied was defined as “child rarely walks on tiptoe”), 67% vs 25% and 24% for observation and casting groups respectively (P<.05). Three smaller studies (from 13 to 18 subjects) also showed decreased toe-walking at follow-up, regardless of treatment.^2,9,11

There is no convincing evidence that treatment is necessary for this condition. We found no randomized trials of treatment for idiopathic toe-walking and no follow-up studies of sufficient size and duration that evaluate long-term effects of toe walking on the patient later in life.

Recommendations from others

No recommendations or guidelines were found.

Evidence summary

Idiopathic toe-walking is a childhood condition of unknown cause characterized by persistence of a tiptoe gait pattern without evidence of neurologic, orthopedic, or psychiatric disease.¹ The incidence in the general population is not known. Children with idiopathic toe-walking usually have limited ankle dorsiflexion and are able to walk with a heel-strike for short periods when asked to do so. Longitudinal data is lacking to determine whether ankle equinus is the primary cause of idiopathic toe-walking or is a consequence of chronically walking on tiptoes. A family history of toe-walking ranges from 30% to 71% in the literature and is considered a characteristic of idiopathic toe walking.^2-4

Evaluation. An important element of the evaluation of idiopathic toe-walking is to distinguish it from neuromuscular disorders associated with toe-walking, such as mild cerebral palsy. Case series with small numbers of subjects (range=27–41) have used gait electromyography (EMG) to distinguish cerebral palsy from idiopathic toe-walking.^4-6 The overlap in gait EMG values in cerebral palsy and idiopathic toe-walking precludes its use as a differentiating diagnostic test.

The only aspect of EMG testing that has been useful in differentiating cerebral palsy from idiopathic toe-walking is gastrocnemius coactivation during resisted knee extension—a finding indicative of neurologic pathology.^5,6 Kinematic analysis and observation of gait and measurement of ankle range of motion have been studied as diagnostic tools to differentiate idiopathic toe-walking from cerebral palsy.^5-8 In the largest of these 4 studies (23 children with mild cerebral palsy and 22 with idiopathic toe-walking), maximal knee extension occurred at ground contact in the idiopathic toe-walking group whereas in the mild cerebral palsy group, the knee was flexed at ground contact.⁷ Measurement of ankle range of motion is not reliable in distinguishing between idiopathic toe-walking and cerebral palsy groups.^5-7

Treatment. Simple observation, physical therapy, serial casting, and Achilles tendon lengthening surgery have been studied in the treatment of idiopathic toe-walking.^2,3,9-11 In the largest case series (n=136),¹⁰ the frequency of toe-walking decreased in 51% of those in both the observation and casted groups. In this same study, the surgical group had lower rates of toe-walking, but no direct comparisons could be made to the nonsurgical groups because the patients in the surgical group were older and had longer follow-up than the other groups.

In a retrospective comparison³ of observation (which included physical therapy and special shoes), casting, and surgery among 80 children with idiopathic toe-walking, surgery resulted in significantly higher parental satisfaction (satisfied was defined as “child rarely walks on tiptoe”), 67% vs 25% and 24% for observation and casting groups respectively (P<.05). Three smaller studies (from 13 to 18 subjects) also showed decreased toe-walking at follow-up, regardless of treatment.^2,9,11

There is no convincing evidence that treatment is necessary for this condition. We found no randomized trials of treatment for idiopathic toe-walking and no follow-up studies of sufficient size and duration that evaluate long-term effects of toe walking on the patient later in life.

Recommendations from others

No recommendations or guidelines were found.

Evidence summary

Idiopathic toe-walking is a childhood condition of unknown cause characterized by persistence of a tiptoe gait pattern without evidence of neurologic, orthopedic, or psychiatric disease.¹ The incidence in the general population is not known. Children with idiopathic toe-walking usually have limited ankle dorsiflexion and are able to walk with a heel-strike for short periods when asked to do so. Longitudinal data is lacking to determine whether ankle equinus is the primary cause of idiopathic toe-walking or is a consequence of chronically walking on tiptoes. A family history of toe-walking ranges from 30% to 71% in the literature and is considered a characteristic of idiopathic toe walking.^2-4

Evaluation. An important element of the evaluation of idiopathic toe-walking is to distinguish it from neuromuscular disorders associated with toe-walking, such as mild cerebral palsy. Case series with small numbers of subjects (range=27–41) have used gait electromyography (EMG) to distinguish cerebral palsy from idiopathic toe-walking.^4-6 The overlap in gait EMG values in cerebral palsy and idiopathic toe-walking precludes its use as a differentiating diagnostic test.

The only aspect of EMG testing that has been useful in differentiating cerebral palsy from idiopathic toe-walking is gastrocnemius coactivation during resisted knee extension—a finding indicative of neurologic pathology.^5,6 Kinematic analysis and observation of gait and measurement of ankle range of motion have been studied as diagnostic tools to differentiate idiopathic toe-walking from cerebral palsy.^5-8 In the largest of these 4 studies (23 children with mild cerebral palsy and 22 with idiopathic toe-walking), maximal knee extension occurred at ground contact in the idiopathic toe-walking group whereas in the mild cerebral palsy group, the knee was flexed at ground contact.⁷ Measurement of ankle range of motion is not reliable in distinguishing between idiopathic toe-walking and cerebral palsy groups.^5-7

Treatment. Simple observation, physical therapy, serial casting, and Achilles tendon lengthening surgery have been studied in the treatment of idiopathic toe-walking.^2,3,9-11 In the largest case series (n=136),¹⁰ the frequency of toe-walking decreased in 51% of those in both the observation and casted groups. In this same study, the surgical group had lower rates of toe-walking, but no direct comparisons could be made to the nonsurgical groups because the patients in the surgical group were older and had longer follow-up than the other groups.

In a retrospective comparison³ of observation (which included physical therapy and special shoes), casting, and surgery among 80 children with idiopathic toe-walking, surgery resulted in significantly higher parental satisfaction (satisfied was defined as “child rarely walks on tiptoe”), 67% vs 25% and 24% for observation and casting groups respectively (P<.05). Three smaller studies (from 13 to 18 subjects) also showed decreased toe-walking at follow-up, regardless of treatment.^2,9,11

There is no convincing evidence that treatment is necessary for this condition. We found no randomized trials of treatment for idiopathic toe-walking and no follow-up studies of sufficient size and duration that evaluate long-term effects of toe walking on the patient later in life.

Recommendations from others

No recommendations or guidelines were found.

Evidence summary

Clinicians have been concerned about x-ray exposure during pregnancy since the 1950s. Much of this concern was based on the Oxford Survey of Childhood Leukemia, as well as other early case-control studies.^1-3 These studies reported an approximate 40% increase in the risk of childhood leukemia among offspring of women who received diagnostic x-rays in pregnancy. However, by modern standards, these studies are of poor quality as they are limited by reliance on maternal recall of prenatal x-ray exposure, lack of consideration for multiple confounding factors, lack of blinding in determination of exposure and outcome status, limitations in selection of both cases and controls, and other significant methodological flaws.

Modern, well-designed studies have failed to replicate the association between in utero radiation and childhood malignancies found in the early studies. We found 1 good-quality and 5 fair-quality case-control studies examining the association between in utero x-ray exposure and childhood leukemia, as well as 6 fair-quality case-control studies examining the association with other childhood malignancies. These studies found no significant association between in utero exposure to any x-ray in general, or to abdominal or pelvic x-rays and development of subsequent childhood leukemia, central nervous system tumors or other malignancies (TABLE).

No meta-analyses, randomized controlled trials, cohort studies or good- or fair-quality case-control studies were found examining in utero x-rays and decreased head circumference, congenital malformations, spontaneous abortion, low birth weight, or developmental problems. One recent, fair-quality case-control study found an association between prenatal dental x-rays and low birth weight (odds ratio [OR]=1.8 [95% confidence interval, 1.09–1.36]) for radiation exposures above 0.4 Gy.⁴ However, this study has been criticized for several reasons, including lack of biological plausibility and failure to control for dental disease.⁵

There does not appear to be an increased risk of adverse pregnancy outcomes with prenatal endoscopic retrograde cholangiopancreaticogram (ERCP), though this conclusion is based on 2 incomplete case series reports with no follow-up of the infants after delivery.^6,7 No good- or fair-quality studies were found examining the association between other diagnostic radiation exposures (CT scan, mammography, positron emission tomography scan, dual-energy x-ray absorptiometry [DEXA]) with adverse pregnancy outcomes.

TABLE
Risk of childhood malignancy after in utero diagnostic X-ray studies¹

Recommendations from others

The American College of Obstetricians and Gynecologists recommends that women be counseled that x-ray exposure from a single diagnostic procedure does not result in harmful fetal effects. Concern about possible effects of ionizing radiation exposure should not prevent medically indicated diagnostic x-ray procedures from being performed on a pregnant woman.⁸

Evidence summary

Clinicians have been concerned about x-ray exposure during pregnancy since the 1950s. Much of this concern was based on the Oxford Survey of Childhood Leukemia, as well as other early case-control studies.^1-3 These studies reported an approximate 40% increase in the risk of childhood leukemia among offspring of women who received diagnostic x-rays in pregnancy. However, by modern standards, these studies are of poor quality as they are limited by reliance on maternal recall of prenatal x-ray exposure, lack of consideration for multiple confounding factors, lack of blinding in determination of exposure and outcome status, limitations in selection of both cases and controls, and other significant methodological flaws.

Modern, well-designed studies have failed to replicate the association between in utero radiation and childhood malignancies found in the early studies. We found 1 good-quality and 5 fair-quality case-control studies examining the association between in utero x-ray exposure and childhood leukemia, as well as 6 fair-quality case-control studies examining the association with other childhood malignancies. These studies found no significant association between in utero exposure to any x-ray in general, or to abdominal or pelvic x-rays and development of subsequent childhood leukemia, central nervous system tumors or other malignancies (TABLE).

No meta-analyses, randomized controlled trials, cohort studies or good- or fair-quality case-control studies were found examining in utero x-rays and decreased head circumference, congenital malformations, spontaneous abortion, low birth weight, or developmental problems. One recent, fair-quality case-control study found an association between prenatal dental x-rays and low birth weight (odds ratio [OR]=1.8 [95% confidence interval, 1.09–1.36]) for radiation exposures above 0.4 Gy.⁴ However, this study has been criticized for several reasons, including lack of biological plausibility and failure to control for dental disease.⁵

There does not appear to be an increased risk of adverse pregnancy outcomes with prenatal endoscopic retrograde cholangiopancreaticogram (ERCP), though this conclusion is based on 2 incomplete case series reports with no follow-up of the infants after delivery.^6,7 No good- or fair-quality studies were found examining the association between other diagnostic radiation exposures (CT scan, mammography, positron emission tomography scan, dual-energy x-ray absorptiometry [DEXA]) with adverse pregnancy outcomes.

TABLE
Risk of childhood malignancy after in utero diagnostic X-ray studies¹

Recommendations from others

The American College of Obstetricians and Gynecologists recommends that women be counseled that x-ray exposure from a single diagnostic procedure does not result in harmful fetal effects. Concern about possible effects of ionizing radiation exposure should not prevent medically indicated diagnostic x-ray procedures from being performed on a pregnant woman.⁸

Evidence summary

Clinicians have been concerned about x-ray exposure during pregnancy since the 1950s. Much of this concern was based on the Oxford Survey of Childhood Leukemia, as well as other early case-control studies.^1-3 These studies reported an approximate 40% increase in the risk of childhood leukemia among offspring of women who received diagnostic x-rays in pregnancy. However, by modern standards, these studies are of poor quality as they are limited by reliance on maternal recall of prenatal x-ray exposure, lack of consideration for multiple confounding factors, lack of blinding in determination of exposure and outcome status, limitations in selection of both cases and controls, and other significant methodological flaws.

Modern, well-designed studies have failed to replicate the association between in utero radiation and childhood malignancies found in the early studies. We found 1 good-quality and 5 fair-quality case-control studies examining the association between in utero x-ray exposure and childhood leukemia, as well as 6 fair-quality case-control studies examining the association with other childhood malignancies. These studies found no significant association between in utero exposure to any x-ray in general, or to abdominal or pelvic x-rays and development of subsequent childhood leukemia, central nervous system tumors or other malignancies (TABLE).

No meta-analyses, randomized controlled trials, cohort studies or good- or fair-quality case-control studies were found examining in utero x-rays and decreased head circumference, congenital malformations, spontaneous abortion, low birth weight, or developmental problems. One recent, fair-quality case-control study found an association between prenatal dental x-rays and low birth weight (odds ratio [OR]=1.8 [95% confidence interval, 1.09–1.36]) for radiation exposures above 0.4 Gy.⁴ However, this study has been criticized for several reasons, including lack of biological plausibility and failure to control for dental disease.⁵

There does not appear to be an increased risk of adverse pregnancy outcomes with prenatal endoscopic retrograde cholangiopancreaticogram (ERCP), though this conclusion is based on 2 incomplete case series reports with no follow-up of the infants after delivery.^6,7 No good- or fair-quality studies were found examining the association between other diagnostic radiation exposures (CT scan, mammography, positron emission tomography scan, dual-energy x-ray absorptiometry [DEXA]) with adverse pregnancy outcomes.

TABLE
Risk of childhood malignancy after in utero diagnostic X-ray studies¹

Recommendations from others

The American College of Obstetricians and Gynecologists recommends that women be counseled that x-ray exposure from a single diagnostic procedure does not result in harmful fetal effects. Concern about possible effects of ionizing radiation exposure should not prevent medically indicated diagnostic x-ray procedures from being performed on a pregnant woman.⁸

Evidence summary

Solar ultraviolet (UV) rays are grouped into 2 wavelengths: UVB (290–320 nm) causes acute inflammation, pain and erythema of sunburn; UVA (320–400 nm) is implicated in long-term damage to the skin, including photoaging and skin cancer, following carcinogenic induction by UVB.¹ Sun protection factor (SPF) refers to the dose of UVB required to produce erythema in protected skin vs unprotected skin.¹ UVA protection is offered in broad-spectrum sunscreens, but is not reflected by the SPF.

SPF-15 is considered by experts to be adequate to prevent sunburn, assuming use of a 2 mg/cm² layer of sunscreen (typically, 30 cc for an average adult). However, observations suggest people apply less than half that.² Most experts recommend reapplication every 2 to 3 hours, though the quantity of sunscreen applied may be more important. A paired, split-body study of children receiving supervised single vs multiple applications of SPF-25 sunscreen to randomly assigned lateral halves of their bodies found protection to be equal for 6 hours of direct sunlight exposure. When the study was repeated with 8 hours of exposure, half the children developed mild erythema on the side with 1 application.³

Because of the causal link between exposure to solar UV radiation and skin cancers, experts believe that sunscreens protect the wearer against the development of skin cancer. Case-control studies demonstrate that sunburn in childhood raises the risk of melanotic and nonmelanotic skin cancers, particularly among those with fair skin.⁴ However, studies of sunscreen’s ability to prevent skin cancer are limited due to variability in use, sun exposure, and susceptibility factors. A randomized controlled trial in adults supports that daily sunscreen use reduces the risk of squamous cell carcinoma but not basal cell carcinoma (number needed to treat=884 for 4.5 years).⁵

Sunscreen permits longer sun exposure and may increase the development of nevi, known to be associated with malignant melanoma risk.^6,7 A retrospective study of 6- to 7-year-old children found that sunscreen use correlated with an increasing number of nevi, though wearing clothing to cover skin while in the sun was protective.⁶ However, a randomized controlled trial (RCT) demonstrated that regular use of broad-spectrum sunscreen in young school-aged children resulted in fewer melanotic nevi compared with controls.⁷ A meta-analysis of 18 observational studies did not show an association between sunscreen use and melanoma incidence.⁸

Sunscreens can cause skin irritation or allergic reaction to either the active ingredient or vehicle.^9,10 A RCT of 603 adults found no allergic reactions to active sunscreen ingredients, though 19% of subjects had an irritant reaction or allergy to the base compounds.⁹ Because infants’ skin may have different absorptive characteristics from that of older children, the US Food and Drug Administration recommends avoiding sunscreen before 6 months of age. As research is lacking for this age group, and the risk of harm due to sunburn is real, it would be reasonably prudent to use sunscreen when physical protection from the sun is impossible, and to avoid ingredients that caused a previous reaction.

Recommendations from others

The Centers for Disease Control and Prevention¹⁰ and the American Academy of Pediatrics¹¹ recommend protection from sun exposure for all children and adolescents, including regular and adequate use of broad-spectrum sunscreen for children over 6 months, protective clothing, and sunglasses. The US Preventive Services Task Force¹² reports that evidence is insufficient to recommend for or against counseling by primary care clinicians to prevent skin cancer.

Evidence summary

Solar ultraviolet (UV) rays are grouped into 2 wavelengths: UVB (290–320 nm) causes acute inflammation, pain and erythema of sunburn; UVA (320–400 nm) is implicated in long-term damage to the skin, including photoaging and skin cancer, following carcinogenic induction by UVB.¹ Sun protection factor (SPF) refers to the dose of UVB required to produce erythema in protected skin vs unprotected skin.¹ UVA protection is offered in broad-spectrum sunscreens, but is not reflected by the SPF.

SPF-15 is considered by experts to be adequate to prevent sunburn, assuming use of a 2 mg/cm² layer of sunscreen (typically, 30 cc for an average adult). However, observations suggest people apply less than half that.² Most experts recommend reapplication every 2 to 3 hours, though the quantity of sunscreen applied may be more important. A paired, split-body study of children receiving supervised single vs multiple applications of SPF-25 sunscreen to randomly assigned lateral halves of their bodies found protection to be equal for 6 hours of direct sunlight exposure. When the study was repeated with 8 hours of exposure, half the children developed mild erythema on the side with 1 application.³

Because of the causal link between exposure to solar UV radiation and skin cancers, experts believe that sunscreens protect the wearer against the development of skin cancer. Case-control studies demonstrate that sunburn in childhood raises the risk of melanotic and nonmelanotic skin cancers, particularly among those with fair skin.⁴ However, studies of sunscreen’s ability to prevent skin cancer are limited due to variability in use, sun exposure, and susceptibility factors. A randomized controlled trial in adults supports that daily sunscreen use reduces the risk of squamous cell carcinoma but not basal cell carcinoma (number needed to treat=884 for 4.5 years).⁵

Sunscreen permits longer sun exposure and may increase the development of nevi, known to be associated with malignant melanoma risk.^6,7 A retrospective study of 6- to 7-year-old children found that sunscreen use correlated with an increasing number of nevi, though wearing clothing to cover skin while in the sun was protective.⁶ However, a randomized controlled trial (RCT) demonstrated that regular use of broad-spectrum sunscreen in young school-aged children resulted in fewer melanotic nevi compared with controls.⁷ A meta-analysis of 18 observational studies did not show an association between sunscreen use and melanoma incidence.⁸

Sunscreens can cause skin irritation or allergic reaction to either the active ingredient or vehicle.^9,10 A RCT of 603 adults found no allergic reactions to active sunscreen ingredients, though 19% of subjects had an irritant reaction or allergy to the base compounds.⁹ Because infants’ skin may have different absorptive characteristics from that of older children, the US Food and Drug Administration recommends avoiding sunscreen before 6 months of age. As research is lacking for this age group, and the risk of harm due to sunburn is real, it would be reasonably prudent to use sunscreen when physical protection from the sun is impossible, and to avoid ingredients that caused a previous reaction.

Recommendations from others

The Centers for Disease Control and Prevention¹⁰ and the American Academy of Pediatrics¹¹ recommend protection from sun exposure for all children and adolescents, including regular and adequate use of broad-spectrum sunscreen for children over 6 months, protective clothing, and sunglasses. The US Preventive Services Task Force¹² reports that evidence is insufficient to recommend for or against counseling by primary care clinicians to prevent skin cancer.

Evidence summary

Solar ultraviolet (UV) rays are grouped into 2 wavelengths: UVB (290–320 nm) causes acute inflammation, pain and erythema of sunburn; UVA (320–400 nm) is implicated in long-term damage to the skin, including photoaging and skin cancer, following carcinogenic induction by UVB.¹ Sun protection factor (SPF) refers to the dose of UVB required to produce erythema in protected skin vs unprotected skin.¹ UVA protection is offered in broad-spectrum sunscreens, but is not reflected by the SPF.

SPF-15 is considered by experts to be adequate to prevent sunburn, assuming use of a 2 mg/cm² layer of sunscreen (typically, 30 cc for an average adult). However, observations suggest people apply less than half that.² Most experts recommend reapplication every 2 to 3 hours, though the quantity of sunscreen applied may be more important. A paired, split-body study of children receiving supervised single vs multiple applications of SPF-25 sunscreen to randomly assigned lateral halves of their bodies found protection to be equal for 6 hours of direct sunlight exposure. When the study was repeated with 8 hours of exposure, half the children developed mild erythema on the side with 1 application.³

Because of the causal link between exposure to solar UV radiation and skin cancers, experts believe that sunscreens protect the wearer against the development of skin cancer. Case-control studies demonstrate that sunburn in childhood raises the risk of melanotic and nonmelanotic skin cancers, particularly among those with fair skin.⁴ However, studies of sunscreen’s ability to prevent skin cancer are limited due to variability in use, sun exposure, and susceptibility factors. A randomized controlled trial in adults supports that daily sunscreen use reduces the risk of squamous cell carcinoma but not basal cell carcinoma (number needed to treat=884 for 4.5 years).⁵

Sunscreen permits longer sun exposure and may increase the development of nevi, known to be associated with malignant melanoma risk.^6,7 A retrospective study of 6- to 7-year-old children found that sunscreen use correlated with an increasing number of nevi, though wearing clothing to cover skin while in the sun was protective.⁶ However, a randomized controlled trial (RCT) demonstrated that regular use of broad-spectrum sunscreen in young school-aged children resulted in fewer melanotic nevi compared with controls.⁷ A meta-analysis of 18 observational studies did not show an association between sunscreen use and melanoma incidence.⁸

Sunscreens can cause skin irritation or allergic reaction to either the active ingredient or vehicle.^9,10 A RCT of 603 adults found no allergic reactions to active sunscreen ingredients, though 19% of subjects had an irritant reaction or allergy to the base compounds.⁹ Because infants’ skin may have different absorptive characteristics from that of older children, the US Food and Drug Administration recommends avoiding sunscreen before 6 months of age. As research is lacking for this age group, and the risk of harm due to sunburn is real, it would be reasonably prudent to use sunscreen when physical protection from the sun is impossible, and to avoid ingredients that caused a previous reaction.

Recommendations from others

The Centers for Disease Control and Prevention¹⁰ and the American Academy of Pediatrics¹¹ recommend protection from sun exposure for all children and adolescents, including regular and adequate use of broad-spectrum sunscreen for children over 6 months, protective clothing, and sunglasses. The US Preventive Services Task Force¹² reports that evidence is insufficient to recommend for or against counseling by primary care clinicians to prevent skin cancer.

Evidence summary

Mild cognitive impairment is defined as memory loss that is out of proportion to that expected for one’s age but which does not meet the clinical criteria for dementia. The diagnosis of dementia requires cognitive impairment plus functional impairment. In mild cognitive impairment, function is preserved by definition.

Several studies have shown that patients with mild cognitive impairment progress to Alzheimer’s disease at a higher rate than normal elderly patients.^2,3 Research has focused on therapies that have shown a positive benefit for patients with Alzheimer’s disease.^4,5 Cholinesterase inhibitors, including donepezil, have shown some benefit in cognition and function for patients with mild to moderate Alzheimer’s disease. Two randomized controlled trials (RCTs) address the effect of donepezil on mild cognitive impairment.

The National Institute of Aging conducted a double-blind RCT multicenter study, which enrolled a total of 769 subjects with mild cognitive impairment. The primary outcome was the development of possible or probable Alzheimer’s disease, and secondary outcomes included cognition and function. Subjects were randomly assigned to receive 2000 IU of vitamin E, 10 mg of donepezil, or placebo daily for 3 years. Of the total, 214 (28%) of the study subjects progressed to dementia, with 212 classified as possible or probable Alzheimer’s disease. Analysis of the treatment effects at 6-month intervals showed a decreased probability of progression to Alzheimer’s disease in the donepezil group during the first 12 months of the study, compared with placebo (14.7% vs 6.3%; P=.04; number needed to treat [NNT]=12), but this change did not persist to 3 years.

Several of the psychometric tests showed statistically significant differences (scores for Mini-Mental State Examination [MMSE], Clinical Dementia Rating [CDR] sum of boxes, Global Deterioration Scale, and modified Alzheimer’s disease Assessment Scale-cognitive subscale [ADAS-cog]) early in the study, but the effect was only detected in the first 12 months of the study.^6,7 The donepezil group had significantly higher rates diarrhea, muscle cramps, insomnia, nausea, and abnormal dreams (P<.01). There was no difference in discontinuation rates between the groups.⁷

The second study was a 24-week multicenter RCT, which included 270 patients with amnestic mild cognitive impairment. Patients were randomized to receive placebo or donepezil (5 mg/d for 42 days, followed by 10 mg/d). The primary end-points were changes on the New York University Paragraph Delayed Recall test and the Alzheimer’s disease Cooperative Study Clinician’s Global Impression of Change for Mild Cognitive Impairment (ADCS CGIC-MCI). No significant differences were found in the primary endpoints at 24 weeks—32.6% in the donepezil group vs 24.3 % in the placebo group showed minimal or moderate improvement, and 51.7% in the donepezil group vs 60.4% in the placebo group showed no change. Secondary endpoints included the modified ADAS-cog, the Patient global Assessment (PGA) and other neuropsychological tests.

The ADAS-cog focuses on psychomotor speed and attention tests. Analysis of the ADAS-cog favored the donepezil group, with 22.3% showing a ≥7-point score vs 12.1% in the placebo group. There were no significant differences on the PGA in the intention-to-treat analysis.8 The donepezil group had a higher rate of adverse drug reactions (P<.03) including diarrhea, nausea, vomiting, leg cramps, and abnormal dreams. The discontinuation rate was 22% in the donepezil group compared with 8% in the placebo group (number needed to harm=7).⁸

Recommendations from others

We found no recommendations about using cholinesterase inhibitors in mild cognitive impairment.

Evidence summary

Mild cognitive impairment is defined as memory loss that is out of proportion to that expected for one’s age but which does not meet the clinical criteria for dementia. The diagnosis of dementia requires cognitive impairment plus functional impairment. In mild cognitive impairment, function is preserved by definition.

Several studies have shown that patients with mild cognitive impairment progress to Alzheimer’s disease at a higher rate than normal elderly patients.^2,3 Research has focused on therapies that have shown a positive benefit for patients with Alzheimer’s disease.^4,5 Cholinesterase inhibitors, including donepezil, have shown some benefit in cognition and function for patients with mild to moderate Alzheimer’s disease. Two randomized controlled trials (RCTs) address the effect of donepezil on mild cognitive impairment.

The National Institute of Aging conducted a double-blind RCT multicenter study, which enrolled a total of 769 subjects with mild cognitive impairment. The primary outcome was the development of possible or probable Alzheimer’s disease, and secondary outcomes included cognition and function. Subjects were randomly assigned to receive 2000 IU of vitamin E, 10 mg of donepezil, or placebo daily for 3 years. Of the total, 214 (28%) of the study subjects progressed to dementia, with 212 classified as possible or probable Alzheimer’s disease. Analysis of the treatment effects at 6-month intervals showed a decreased probability of progression to Alzheimer’s disease in the donepezil group during the first 12 months of the study, compared with placebo (14.7% vs 6.3%; P=.04; number needed to treat [NNT]=12), but this change did not persist to 3 years.

Several of the psychometric tests showed statistically significant differences (scores for Mini-Mental State Examination [MMSE], Clinical Dementia Rating [CDR] sum of boxes, Global Deterioration Scale, and modified Alzheimer’s disease Assessment Scale-cognitive subscale [ADAS-cog]) early in the study, but the effect was only detected in the first 12 months of the study.^6,7 The donepezil group had significantly higher rates diarrhea, muscle cramps, insomnia, nausea, and abnormal dreams (P<.01). There was no difference in discontinuation rates between the groups.⁷

The second study was a 24-week multicenter RCT, which included 270 patients with amnestic mild cognitive impairment. Patients were randomized to receive placebo or donepezil (5 mg/d for 42 days, followed by 10 mg/d). The primary end-points were changes on the New York University Paragraph Delayed Recall test and the Alzheimer’s disease Cooperative Study Clinician’s Global Impression of Change for Mild Cognitive Impairment (ADCS CGIC-MCI). No significant differences were found in the primary endpoints at 24 weeks—32.6% in the donepezil group vs 24.3 % in the placebo group showed minimal or moderate improvement, and 51.7% in the donepezil group vs 60.4% in the placebo group showed no change. Secondary endpoints included the modified ADAS-cog, the Patient global Assessment (PGA) and other neuropsychological tests.

The ADAS-cog focuses on psychomotor speed and attention tests. Analysis of the ADAS-cog favored the donepezil group, with 22.3% showing a ≥7-point score vs 12.1% in the placebo group. There were no significant differences on the PGA in the intention-to-treat analysis.8 The donepezil group had a higher rate of adverse drug reactions (P<.03) including diarrhea, nausea, vomiting, leg cramps, and abnormal dreams. The discontinuation rate was 22% in the donepezil group compared with 8% in the placebo group (number needed to harm=7).⁸

Recommendations from others

We found no recommendations about using cholinesterase inhibitors in mild cognitive impairment.

Evidence summary

Mild cognitive impairment is defined as memory loss that is out of proportion to that expected for one’s age but which does not meet the clinical criteria for dementia. The diagnosis of dementia requires cognitive impairment plus functional impairment. In mild cognitive impairment, function is preserved by definition.

Several studies have shown that patients with mild cognitive impairment progress to Alzheimer’s disease at a higher rate than normal elderly patients.^2,3 Research has focused on therapies that have shown a positive benefit for patients with Alzheimer’s disease.^4,5 Cholinesterase inhibitors, including donepezil, have shown some benefit in cognition and function for patients with mild to moderate Alzheimer’s disease. Two randomized controlled trials (RCTs) address the effect of donepezil on mild cognitive impairment.

The National Institute of Aging conducted a double-blind RCT multicenter study, which enrolled a total of 769 subjects with mild cognitive impairment. The primary outcome was the development of possible or probable Alzheimer’s disease, and secondary outcomes included cognition and function. Subjects were randomly assigned to receive 2000 IU of vitamin E, 10 mg of donepezil, or placebo daily for 3 years. Of the total, 214 (28%) of the study subjects progressed to dementia, with 212 classified as possible or probable Alzheimer’s disease. Analysis of the treatment effects at 6-month intervals showed a decreased probability of progression to Alzheimer’s disease in the donepezil group during the first 12 months of the study, compared with placebo (14.7% vs 6.3%; P=.04; number needed to treat [NNT]=12), but this change did not persist to 3 years.

Several of the psychometric tests showed statistically significant differences (scores for Mini-Mental State Examination [MMSE], Clinical Dementia Rating [CDR] sum of boxes, Global Deterioration Scale, and modified Alzheimer’s disease Assessment Scale-cognitive subscale [ADAS-cog]) early in the study, but the effect was only detected in the first 12 months of the study.^6,7 The donepezil group had significantly higher rates diarrhea, muscle cramps, insomnia, nausea, and abnormal dreams (P<.01). There was no difference in discontinuation rates between the groups.⁷

The second study was a 24-week multicenter RCT, which included 270 patients with amnestic mild cognitive impairment. Patients were randomized to receive placebo or donepezil (5 mg/d for 42 days, followed by 10 mg/d). The primary end-points were changes on the New York University Paragraph Delayed Recall test and the Alzheimer’s disease Cooperative Study Clinician’s Global Impression of Change for Mild Cognitive Impairment (ADCS CGIC-MCI). No significant differences were found in the primary endpoints at 24 weeks—32.6% in the donepezil group vs 24.3 % in the placebo group showed minimal or moderate improvement, and 51.7% in the donepezil group vs 60.4% in the placebo group showed no change. Secondary endpoints included the modified ADAS-cog, the Patient global Assessment (PGA) and other neuropsychological tests.

The ADAS-cog focuses on psychomotor speed and attention tests. Analysis of the ADAS-cog favored the donepezil group, with 22.3% showing a ≥7-point score vs 12.1% in the placebo group. There were no significant differences on the PGA in the intention-to-treat analysis.8 The donepezil group had a higher rate of adverse drug reactions (P<.03) including diarrhea, nausea, vomiting, leg cramps, and abnormal dreams. The discontinuation rate was 22% in the donepezil group compared with 8% in the placebo group (number needed to harm=7).⁸

Recommendations from others

We found no recommendations about using cholinesterase inhibitors in mild cognitive impairment.

Evidence summary

Eighteen percent of all women report migraines.¹ Among pregnant migraineurs, 2.5% to 8% reported worsening symptoms.^1,2 Guidelines recommend considering prophylaxis for nonpregnant patients if they experience at least 3 or 4 prolonged severe attacks per month.³

Nonpharmacological treatment. Two studies were published together evaluating thermal biofeedback, relaxation training, and physical therapy exercises. The first, a cohort study, showed alleviation of symptoms for 15 of 19 women. The second, a small unblinded RCT, compared 11 women using the combination treatment with 14 control women who received attention from the therapist but no other intervention. Over 72% of the treatment arm improved compared with nearly 29% of the control group.⁴ The 30 women (19 from the original cohort and the 11 from the intervention arm of the RCT) were then followed as a cohort for the duration of pregnancy and 1 year postpartum. More than 67% of the patients continued to report a decrease in the frequency and severity of headache.⁵ Interpretation of these studies is limited by small sample size and testing in settings with specialized resources that are not found in every community.

Pharmacologic agents. Randomized controlled trials have demonstrated that multiple medications have prophylactic benefit in the treatment of nonpregnant patients with migraine. In particular, propanolol,⁶ divalproex sodium/sodium valproate, and topiramate⁷ have been effective. A single case report on the use of labetalol by a pregnant woman at 28 weeks’ gestational age showed that it was effective in reducing the frequency and severity of her headaches after 1 week of use. This improvement persisted until delivery at 38 weeks.⁸

Safety in pregnancy. The Food and Drug Administration (FDA) assigns fetal risk categories to all drugs based on controlled studies in humans, animal reproduction studies, and surveillance studies.⁹ There are no data about the effectiveness of medications for migraine prophylaxis in pregnancy so one cannot select a specific medication with certainty. However, it may be reasonable to select medications based on both effectiveness for nonpregnant patients and established safety as determined by the FDA’s fetal risk summary.

The TABLE shows commonly used drugs for prophylaxis of migraine and their pregnancy risk category classification. It should be noted that even if risk has been demonstrated in a medication, not all risks are equal. For example, propanolol is class D because of increased risk for intrauterine growth restriction in the third trimester, while sodium valproate is class D because of known teratogenicity.⁹

TABLE
Pregnancy risk category of some prophylactic drugs for migraine

Recommendations from others

Practice guidelines published by the American Academy of Neurology recommend avoidance of prophylactic medications in pregnancy, if possible. They also recommend nonpharmacologic treatment as an acceptable option in pregnancy. If drug treatment is necessary, they recommend selecting an agent with the lowest risk of adverse effects to the fetus.³ Most review articles state that, if medication is necessary, it should be tailored towards other comorbidities, if possible; if there are no coexisting conditions, then calcium channel blockers or beta blockers would be the treatment of choice, based on safety data.^1,10

Evidence summary

Eighteen percent of all women report migraines.¹ Among pregnant migraineurs, 2.5% to 8% reported worsening symptoms.^1,2 Guidelines recommend considering prophylaxis for nonpregnant patients if they experience at least 3 or 4 prolonged severe attacks per month.³

Nonpharmacological treatment. Two studies were published together evaluating thermal biofeedback, relaxation training, and physical therapy exercises. The first, a cohort study, showed alleviation of symptoms for 15 of 19 women. The second, a small unblinded RCT, compared 11 women using the combination treatment with 14 control women who received attention from the therapist but no other intervention. Over 72% of the treatment arm improved compared with nearly 29% of the control group.⁴ The 30 women (19 from the original cohort and the 11 from the intervention arm of the RCT) were then followed as a cohort for the duration of pregnancy and 1 year postpartum. More than 67% of the patients continued to report a decrease in the frequency and severity of headache.⁵ Interpretation of these studies is limited by small sample size and testing in settings with specialized resources that are not found in every community.

Pharmacologic agents. Randomized controlled trials have demonstrated that multiple medications have prophylactic benefit in the treatment of nonpregnant patients with migraine. In particular, propanolol,⁶ divalproex sodium/sodium valproate, and topiramate⁷ have been effective. A single case report on the use of labetalol by a pregnant woman at 28 weeks’ gestational age showed that it was effective in reducing the frequency and severity of her headaches after 1 week of use. This improvement persisted until delivery at 38 weeks.⁸

Safety in pregnancy. The Food and Drug Administration (FDA) assigns fetal risk categories to all drugs based on controlled studies in humans, animal reproduction studies, and surveillance studies.⁹ There are no data about the effectiveness of medications for migraine prophylaxis in pregnancy so one cannot select a specific medication with certainty. However, it may be reasonable to select medications based on both effectiveness for nonpregnant patients and established safety as determined by the FDA’s fetal risk summary.

The TABLE shows commonly used drugs for prophylaxis of migraine and their pregnancy risk category classification. It should be noted that even if risk has been demonstrated in a medication, not all risks are equal. For example, propanolol is class D because of increased risk for intrauterine growth restriction in the third trimester, while sodium valproate is class D because of known teratogenicity.⁹

TABLE
Pregnancy risk category of some prophylactic drugs for migraine

Recommendations from others

Practice guidelines published by the American Academy of Neurology recommend avoidance of prophylactic medications in pregnancy, if possible. They also recommend nonpharmacologic treatment as an acceptable option in pregnancy. If drug treatment is necessary, they recommend selecting an agent with the lowest risk of adverse effects to the fetus.³ Most review articles state that, if medication is necessary, it should be tailored towards other comorbidities, if possible; if there are no coexisting conditions, then calcium channel blockers or beta blockers would be the treatment of choice, based on safety data.^1,10

Evidence summary

Eighteen percent of all women report migraines.¹ Among pregnant migraineurs, 2.5% to 8% reported worsening symptoms.^1,2 Guidelines recommend considering prophylaxis for nonpregnant patients if they experience at least 3 or 4 prolonged severe attacks per month.³

Nonpharmacological treatment. Two studies were published together evaluating thermal biofeedback, relaxation training, and physical therapy exercises. The first, a cohort study, showed alleviation of symptoms for 15 of 19 women. The second, a small unblinded RCT, compared 11 women using the combination treatment with 14 control women who received attention from the therapist but no other intervention. Over 72% of the treatment arm improved compared with nearly 29% of the control group.⁴ The 30 women (19 from the original cohort and the 11 from the intervention arm of the RCT) were then followed as a cohort for the duration of pregnancy and 1 year postpartum. More than 67% of the patients continued to report a decrease in the frequency and severity of headache.⁵ Interpretation of these studies is limited by small sample size and testing in settings with specialized resources that are not found in every community.

Pharmacologic agents. Randomized controlled trials have demonstrated that multiple medications have prophylactic benefit in the treatment of nonpregnant patients with migraine. In particular, propanolol,⁶ divalproex sodium/sodium valproate, and topiramate⁷ have been effective. A single case report on the use of labetalol by a pregnant woman at 28 weeks’ gestational age showed that it was effective in reducing the frequency and severity of her headaches after 1 week of use. This improvement persisted until delivery at 38 weeks.⁸

Safety in pregnancy. The Food and Drug Administration (FDA) assigns fetal risk categories to all drugs based on controlled studies in humans, animal reproduction studies, and surveillance studies.⁹ There are no data about the effectiveness of medications for migraine prophylaxis in pregnancy so one cannot select a specific medication with certainty. However, it may be reasonable to select medications based on both effectiveness for nonpregnant patients and established safety as determined by the FDA’s fetal risk summary.

The TABLE shows commonly used drugs for prophylaxis of migraine and their pregnancy risk category classification. It should be noted that even if risk has been demonstrated in a medication, not all risks are equal. For example, propanolol is class D because of increased risk for intrauterine growth restriction in the third trimester, while sodium valproate is class D because of known teratogenicity.⁹

TABLE
Pregnancy risk category of some prophylactic drugs for migraine

Recommendations from others

Practice guidelines published by the American Academy of Neurology recommend avoidance of prophylactic medications in pregnancy, if possible. They also recommend nonpharmacologic treatment as an acceptable option in pregnancy. If drug treatment is necessary, they recommend selecting an agent with the lowest risk of adverse effects to the fetus.³ Most review articles state that, if medication is necessary, it should be tailored towards other comorbidities, if possible; if there are no coexisting conditions, then calcium channel blockers or beta blockers would be the treatment of choice, based on safety data.^1,10