Clinical Inquiries

Evidence summary

The ideal H pylori eradication regimen should reach an intention-to-treat cure rate of 80% (Table).¹ Effective regimens are:

Fourteen-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A meta-analysis of 13 studies found the eradication rate for 14-day therapy was 81% (95% confidence interval [CI], 77%–85%), compared with 72% (95% CI, 68%–76%) for 7-day therapy. The eradication rate for 10-day therapy (83%; 95% CI, 75%–89%), however, was not significantly better than that for 7-day therapy (80%; 95% CI, 71%–86%).² Side effects were more frequent in the longer therapies, but did not lead to discontinuation of therapy.

Seven-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A high-quality systematic review of 82 studies using 7-day triple therapy found clarithromycin 500 twice daily yielded a higher eradication rate than clarithromycin 250 mg twice daily when combined with a PPI and amoxicillin (87% vs 81%; P<.0001). When clarithromycin was combined with a PPI and metronidazole, the higher dose of clarithromycin did not yield significantly higher eradication rates (88% vs 89%, P=.259).³

Seven-day triple therapy of ranitidine bismuth citrate + clarithromycin + metronidazole or amoxicillin. For these therapies, a high-quality systematic review of 8 studies reported eradication rates of 81% (95% CI, 77%–84%) with amoxicillin and 88% (95% CI, 85%–90%) with metronidazole.^4,5 Side effects were not reported in a uniform manner for the 7-day therapies, but were noted to be mild and did not lead to significant discontinuation of therapy. Pooled dropout rates were similar among all regimens.⁴

Three-day quadruple therapy of PPI + bismuth + clarithromycin + metronidazole or PPI+ clarithromycin + amoxicillin + metronidazole. An otherwise high-quality but unblinded randomized clinical trial of 234 patients demonstrated that 2 days of pretreatment with lansoprazole followed by 3 days of lansoprazole with clarithromycin, amoxicillin, and metronidazole yielded eradication rates comparable with 5-day treatment (81% vs. 89%; P<.05).⁶

Another randomized clinical trial of 118 patients, blinded to investigators but not patients, showed that quadruple 3-day therapy with lansoprazole + bismuth + clarithromycin + metronidazole was as effective as 7 days of lansoprazole + clarithromycin + metronidazole (87% vs 86%; P=.94), and had significantly shorter duration of side effects (2.6 vs 6.2 days; P<.001). Eradication rates were similar in isolates that were resistant or sensitive to either metronidazole or clarithromycin.⁷

The problems of emerging clarithromycin and metronidazole resistance have not been

extensively studied. In 1 review, metronida-zole-containing regimens eradicated metronidazole-sensitive strains more effectively than metronidazole-resistant strains (weighted difference, 15%; 95% CI, 8%–20%).⁴ When an infection is resistant to metronidazole, amoxicillin should be used instead.⁴ In areas of high clarithromycin and metronidazole resistance, a quadruple regimen might be more effective.⁷

TABLE
Effective therapies for Heliobacter pylorieradication

Recommendations from others

The Maastricht Consensus of the European Heliobacter Study Group¹ recommends a 7-day triple regimen of PPI + clarithromycin + either metronidazole or amoxicillin or (if clarithromycin resistance is prevalent) PPI + amoxicillin 500 mg 3 times daily + metronidazole 500 mg 3 times daily.

The American College of Gastroenterology recommends 14-day therapy of one of the following options:⁸

• PPI + clarithromycin + (metronidazole or amoxicillin), or ranitidine bismuth citrate + clarithromycin + (metronidazole or amoxicillin). Tetracycline 500 mg twice a day can be substituted for amoxicillin or metronidazole
• PPI + bismuth subsalicylate 525 mg + metronidazole 500 mg 3 times daily + tetra-cycline 500 mg 4 times daily
• Bismuth subsalicylate 525 mg 4 times daily + metronidazole 250 mg 4 times daily + tetra-cycline 500 mg 4 times daily + H2 receptor antagonist in standard acid-suppression dose (eg, famotidine 20 mg twice a day for 4 weeks).

The Institute for Clinical Systems Improvement recommends as first-choice treatment a 7-day PPI/clarithromycin/amoxicillin combination, and as second choice a 7-day regimen of PPI, tetracycline 250 mg 4 times daily, metronidazole 500 mg twice daily, and bismuth subsalicylate 525 mg 4 times daily.⁹

Evidence summary

The ideal H pylori eradication regimen should reach an intention-to-treat cure rate of 80% (Table).¹ Effective regimens are:

Fourteen-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A meta-analysis of 13 studies found the eradication rate for 14-day therapy was 81% (95% confidence interval [CI], 77%–85%), compared with 72% (95% CI, 68%–76%) for 7-day therapy. The eradication rate for 10-day therapy (83%; 95% CI, 75%–89%), however, was not significantly better than that for 7-day therapy (80%; 95% CI, 71%–86%).² Side effects were more frequent in the longer therapies, but did not lead to discontinuation of therapy.

Seven-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A high-quality systematic review of 82 studies using 7-day triple therapy found clarithromycin 500 twice daily yielded a higher eradication rate than clarithromycin 250 mg twice daily when combined with a PPI and amoxicillin (87% vs 81%; P<.0001). When clarithromycin was combined with a PPI and metronidazole, the higher dose of clarithromycin did not yield significantly higher eradication rates (88% vs 89%, P=.259).³

Seven-day triple therapy of ranitidine bismuth citrate + clarithromycin + metronidazole or amoxicillin. For these therapies, a high-quality systematic review of 8 studies reported eradication rates of 81% (95% CI, 77%–84%) with amoxicillin and 88% (95% CI, 85%–90%) with metronidazole.^4,5 Side effects were not reported in a uniform manner for the 7-day therapies, but were noted to be mild and did not lead to significant discontinuation of therapy. Pooled dropout rates were similar among all regimens.⁴

Three-day quadruple therapy of PPI + bismuth + clarithromycin + metronidazole or PPI+ clarithromycin + amoxicillin + metronidazole. An otherwise high-quality but unblinded randomized clinical trial of 234 patients demonstrated that 2 days of pretreatment with lansoprazole followed by 3 days of lansoprazole with clarithromycin, amoxicillin, and metronidazole yielded eradication rates comparable with 5-day treatment (81% vs. 89%; P<.05).⁶

Another randomized clinical trial of 118 patients, blinded to investigators but not patients, showed that quadruple 3-day therapy with lansoprazole + bismuth + clarithromycin + metronidazole was as effective as 7 days of lansoprazole + clarithromycin + metronidazole (87% vs 86%; P=.94), and had significantly shorter duration of side effects (2.6 vs 6.2 days; P<.001). Eradication rates were similar in isolates that were resistant or sensitive to either metronidazole or clarithromycin.⁷

The problems of emerging clarithromycin and metronidazole resistance have not been

extensively studied. In 1 review, metronida-zole-containing regimens eradicated metronidazole-sensitive strains more effectively than metronidazole-resistant strains (weighted difference, 15%; 95% CI, 8%–20%).⁴ When an infection is resistant to metronidazole, amoxicillin should be used instead.⁴ In areas of high clarithromycin and metronidazole resistance, a quadruple regimen might be more effective.⁷

TABLE
Effective therapies for Heliobacter pylorieradication

Recommendations from others

The Maastricht Consensus of the European Heliobacter Study Group¹ recommends a 7-day triple regimen of PPI + clarithromycin + either metronidazole or amoxicillin or (if clarithromycin resistance is prevalent) PPI + amoxicillin 500 mg 3 times daily + metronidazole 500 mg 3 times daily.

The American College of Gastroenterology recommends 14-day therapy of one of the following options:⁸

• PPI + clarithromycin + (metronidazole or amoxicillin), or ranitidine bismuth citrate + clarithromycin + (metronidazole or amoxicillin). Tetracycline 500 mg twice a day can be substituted for amoxicillin or metronidazole
• PPI + bismuth subsalicylate 525 mg + metronidazole 500 mg 3 times daily + tetra-cycline 500 mg 4 times daily
• Bismuth subsalicylate 525 mg 4 times daily + metronidazole 250 mg 4 times daily + tetra-cycline 500 mg 4 times daily + H2 receptor antagonist in standard acid-suppression dose (eg, famotidine 20 mg twice a day for 4 weeks).

The Institute for Clinical Systems Improvement recommends as first-choice treatment a 7-day PPI/clarithromycin/amoxicillin combination, and as second choice a 7-day regimen of PPI, tetracycline 250 mg 4 times daily, metronidazole 500 mg twice daily, and bismuth subsalicylate 525 mg 4 times daily.⁹

Evidence summary

The ideal H pylori eradication regimen should reach an intention-to-treat cure rate of 80% (Table).¹ Effective regimens are:

Fourteen-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A meta-analysis of 13 studies found the eradication rate for 14-day therapy was 81% (95% confidence interval [CI], 77%–85%), compared with 72% (95% CI, 68%–76%) for 7-day therapy. The eradication rate for 10-day therapy (83%; 95% CI, 75%–89%), however, was not significantly better than that for 7-day therapy (80%; 95% CI, 71%–86%).² Side effects were more frequent in the longer therapies, but did not lead to discontinuation of therapy.

Seven-day triple therapy of PPI + clarithromycin + metronidazole or amoxicillin. A high-quality systematic review of 82 studies using 7-day triple therapy found clarithromycin 500 twice daily yielded a higher eradication rate than clarithromycin 250 mg twice daily when combined with a PPI and amoxicillin (87% vs 81%; P<.0001). When clarithromycin was combined with a PPI and metronidazole, the higher dose of clarithromycin did not yield significantly higher eradication rates (88% vs 89%, P=.259).³

Seven-day triple therapy of ranitidine bismuth citrate + clarithromycin + metronidazole or amoxicillin. For these therapies, a high-quality systematic review of 8 studies reported eradication rates of 81% (95% CI, 77%–84%) with amoxicillin and 88% (95% CI, 85%–90%) with metronidazole.^4,5 Side effects were not reported in a uniform manner for the 7-day therapies, but were noted to be mild and did not lead to significant discontinuation of therapy. Pooled dropout rates were similar among all regimens.⁴

Three-day quadruple therapy of PPI + bismuth + clarithromycin + metronidazole or PPI+ clarithromycin + amoxicillin + metronidazole. An otherwise high-quality but unblinded randomized clinical trial of 234 patients demonstrated that 2 days of pretreatment with lansoprazole followed by 3 days of lansoprazole with clarithromycin, amoxicillin, and metronidazole yielded eradication rates comparable with 5-day treatment (81% vs. 89%; P<.05).⁶

Another randomized clinical trial of 118 patients, blinded to investigators but not patients, showed that quadruple 3-day therapy with lansoprazole + bismuth + clarithromycin + metronidazole was as effective as 7 days of lansoprazole + clarithromycin + metronidazole (87% vs 86%; P=.94), and had significantly shorter duration of side effects (2.6 vs 6.2 days; P<.001). Eradication rates were similar in isolates that were resistant or sensitive to either metronidazole or clarithromycin.⁷

The problems of emerging clarithromycin and metronidazole resistance have not been

extensively studied. In 1 review, metronida-zole-containing regimens eradicated metronidazole-sensitive strains more effectively than metronidazole-resistant strains (weighted difference, 15%; 95% CI, 8%–20%).⁴ When an infection is resistant to metronidazole, amoxicillin should be used instead.⁴ In areas of high clarithromycin and metronidazole resistance, a quadruple regimen might be more effective.⁷

TABLE
Effective therapies for Heliobacter pylorieradication

Recommendations from others

The Maastricht Consensus of the European Heliobacter Study Group¹ recommends a 7-day triple regimen of PPI + clarithromycin + either metronidazole or amoxicillin or (if clarithromycin resistance is prevalent) PPI + amoxicillin 500 mg 3 times daily + metronidazole 500 mg 3 times daily.

The American College of Gastroenterology recommends 14-day therapy of one of the following options:⁸

• PPI + clarithromycin + (metronidazole or amoxicillin), or ranitidine bismuth citrate + clarithromycin + (metronidazole or amoxicillin). Tetracycline 500 mg twice a day can be substituted for amoxicillin or metronidazole
• PPI + bismuth subsalicylate 525 mg + metronidazole 500 mg 3 times daily + tetra-cycline 500 mg 4 times daily
• Bismuth subsalicylate 525 mg 4 times daily + metronidazole 250 mg 4 times daily + tetra-cycline 500 mg 4 times daily + H2 receptor antagonist in standard acid-suppression dose (eg, famotidine 20 mg twice a day for 4 weeks).

The Institute for Clinical Systems Improvement recommends as first-choice treatment a 7-day PPI/clarithromycin/amoxicillin combination, and as second choice a 7-day regimen of PPI, tetracycline 250 mg 4 times daily, metronidazole 500 mg twice daily, and bismuth subsalicylate 525 mg 4 times daily.⁹

Evidence summary

The prevalence of elevated blood lead levels varies widely among different demographic groups and geographic regions, and it has decreased dramatically in the last several decades. Racial and ethnic minorities and children of families with low incomes, who live in the Northeast or Midwest, or who live in older houses continue to be at increased risk.¹ Children with blood lead levels 10 μg/dL have been shown to have poorer cognitive and behavioral functioning.²

No studies have demonstrated that screening for lead poisoning improves outcomes. To justify screening, one must therefore extrapolate from indirect evidence, demonstrating that screening tests are accurate and that treatment of children detected by screening is effective. Capillary blood samples are comparable with venous samples for detecting elevated blood lead levels. The sensitivity of capillary samples ranges from 86% to 96% compared with venous samples.³

In low-prevalence areas, questionnaires may inform screening decisions. A questionnaire inquiring about age of housing, presence of peeling paint, ongoing renovations, siblings or playmates with elevated blood lead levels, adults in the home with occupational exposures to lead, and proximity to industrial sources of lead has a sensitivity for detecting blood lead levels 10 μg/dL ranging from 32% to 87%. Sensitivity varies depending on the population and geographic location in which the questionnaire is tested. Accuracy is improved by tailoring the questionnaire based on locally important risk factors.⁴

Proposed treatments for elevated blood lead levels include chelation therapy, education about hygiene and nutrition, household dust control measures, and soil lead abatement. No good-quality trials have demonstrated that lowering slightly to moderately elevated blood lead levels (10–55 μg/dL) improves patient-oriented outcomes such as cognitive and behavioral functioning. Although 1 observational study of chelation therapy linked lowering blood lead levels with improved cognitive function,³ a randomized controlled trial showed that chelation had no effect on cognitive or behavioral outcomes.⁵

All other trials evaluating treatment for lead poisoning looked at the intermediate outcome of blood lead levels. A systematic review of randomized controlled trials showed that home dust control interventions reduced the proportion of children with elevated blood lead levels (15 μg/dL) from 14% to 6%.⁶ A randomized controlled trial of high-efficiency particulate air (HEPA) filtration vacuuming showed no effect.⁷ More intensive interventions such as soil lead abatement and paint remediation have not proven effective in good-quality randomized controlled trials.

Increasing dietary calcium and iron and decreasing dietary fat are also commonly recommended for children with elevated blood lead levels, based on animal models and cross-sectional studies. The only randomized controlled trial that investigated calcium supplementation showed no effect on blood lead levels.⁸ Our search revealed no good-quality studies on the effect of iron or fat intake on lead poisoning.

In summary, because the prevalence of lead poisoning varies between communities and continues to change, standard recommendations are not possible. Clinicians must rely on local epidemiologic data to make screening decisions. Although questionnaires are accurate in predicting elevated blood lead levels in some settings, no specific set of questions can be recommended for all populations.

No treatment options for those with mild to moderate elevations in blood lead levels have been shown to improve clinically important outcomes, although some interventions may decrease blood lead levels.

Recommendations from others

The Centers for Disease Control and Prevention (CDC) recommends

• that individual states develop screening plans based on local data
• universal screening at 12 and 24 months of age:

Otherwise screening should be targeted based on a questionnaire on age of housing, recent or ongoing remodeling, and having a sibling or playmate diagnosed with lead poisoning, in addition to questions on locally important risk factors.⁹

The American Academy of Pediatrics endorses the CDC recommendations.² The US Preventive Services Task Force, the American Academy of Family Physicians, and the American College of Preventive Medicine all recommend screening for lead poisoning at 12 months of age in children with demographic or geographic risk factors.^3,10,11

Evidence summary

The prevalence of elevated blood lead levels varies widely among different demographic groups and geographic regions, and it has decreased dramatically in the last several decades. Racial and ethnic minorities and children of families with low incomes, who live in the Northeast or Midwest, or who live in older houses continue to be at increased risk.¹ Children with blood lead levels 10 μg/dL have been shown to have poorer cognitive and behavioral functioning.²

No studies have demonstrated that screening for lead poisoning improves outcomes. To justify screening, one must therefore extrapolate from indirect evidence, demonstrating that screening tests are accurate and that treatment of children detected by screening is effective. Capillary blood samples are comparable with venous samples for detecting elevated blood lead levels. The sensitivity of capillary samples ranges from 86% to 96% compared with venous samples.³

In low-prevalence areas, questionnaires may inform screening decisions. A questionnaire inquiring about age of housing, presence of peeling paint, ongoing renovations, siblings or playmates with elevated blood lead levels, adults in the home with occupational exposures to lead, and proximity to industrial sources of lead has a sensitivity for detecting blood lead levels 10 μg/dL ranging from 32% to 87%. Sensitivity varies depending on the population and geographic location in which the questionnaire is tested. Accuracy is improved by tailoring the questionnaire based on locally important risk factors.⁴

Proposed treatments for elevated blood lead levels include chelation therapy, education about hygiene and nutrition, household dust control measures, and soil lead abatement. No good-quality trials have demonstrated that lowering slightly to moderately elevated blood lead levels (10–55 μg/dL) improves patient-oriented outcomes such as cognitive and behavioral functioning. Although 1 observational study of chelation therapy linked lowering blood lead levels with improved cognitive function,³ a randomized controlled trial showed that chelation had no effect on cognitive or behavioral outcomes.⁵

All other trials evaluating treatment for lead poisoning looked at the intermediate outcome of blood lead levels. A systematic review of randomized controlled trials showed that home dust control interventions reduced the proportion of children with elevated blood lead levels (15 μg/dL) from 14% to 6%.⁶ A randomized controlled trial of high-efficiency particulate air (HEPA) filtration vacuuming showed no effect.⁷ More intensive interventions such as soil lead abatement and paint remediation have not proven effective in good-quality randomized controlled trials.

Increasing dietary calcium and iron and decreasing dietary fat are also commonly recommended for children with elevated blood lead levels, based on animal models and cross-sectional studies. The only randomized controlled trial that investigated calcium supplementation showed no effect on blood lead levels.⁸ Our search revealed no good-quality studies on the effect of iron or fat intake on lead poisoning.

In summary, because the prevalence of lead poisoning varies between communities and continues to change, standard recommendations are not possible. Clinicians must rely on local epidemiologic data to make screening decisions. Although questionnaires are accurate in predicting elevated blood lead levels in some settings, no specific set of questions can be recommended for all populations.

No treatment options for those with mild to moderate elevations in blood lead levels have been shown to improve clinically important outcomes, although some interventions may decrease blood lead levels.

Recommendations from others

The Centers for Disease Control and Prevention (CDC) recommends

• that individual states develop screening plans based on local data
• universal screening at 12 and 24 months of age:

Otherwise screening should be targeted based on a questionnaire on age of housing, recent or ongoing remodeling, and having a sibling or playmate diagnosed with lead poisoning, in addition to questions on locally important risk factors.⁹

The American Academy of Pediatrics endorses the CDC recommendations.² The US Preventive Services Task Force, the American Academy of Family Physicians, and the American College of Preventive Medicine all recommend screening for lead poisoning at 12 months of age in children with demographic or geographic risk factors.^3,10,11

Evidence summary

The prevalence of elevated blood lead levels varies widely among different demographic groups and geographic regions, and it has decreased dramatically in the last several decades. Racial and ethnic minorities and children of families with low incomes, who live in the Northeast or Midwest, or who live in older houses continue to be at increased risk.¹ Children with blood lead levels 10 μg/dL have been shown to have poorer cognitive and behavioral functioning.²

No studies have demonstrated that screening for lead poisoning improves outcomes. To justify screening, one must therefore extrapolate from indirect evidence, demonstrating that screening tests are accurate and that treatment of children detected by screening is effective. Capillary blood samples are comparable with venous samples for detecting elevated blood lead levels. The sensitivity of capillary samples ranges from 86% to 96% compared with venous samples.³

In low-prevalence areas, questionnaires may inform screening decisions. A questionnaire inquiring about age of housing, presence of peeling paint, ongoing renovations, siblings or playmates with elevated blood lead levels, adults in the home with occupational exposures to lead, and proximity to industrial sources of lead has a sensitivity for detecting blood lead levels 10 μg/dL ranging from 32% to 87%. Sensitivity varies depending on the population and geographic location in which the questionnaire is tested. Accuracy is improved by tailoring the questionnaire based on locally important risk factors.⁴

Proposed treatments for elevated blood lead levels include chelation therapy, education about hygiene and nutrition, household dust control measures, and soil lead abatement. No good-quality trials have demonstrated that lowering slightly to moderately elevated blood lead levels (10–55 μg/dL) improves patient-oriented outcomes such as cognitive and behavioral functioning. Although 1 observational study of chelation therapy linked lowering blood lead levels with improved cognitive function,³ a randomized controlled trial showed that chelation had no effect on cognitive or behavioral outcomes.⁵

All other trials evaluating treatment for lead poisoning looked at the intermediate outcome of blood lead levels. A systematic review of randomized controlled trials showed that home dust control interventions reduced the proportion of children with elevated blood lead levels (15 μg/dL) from 14% to 6%.⁶ A randomized controlled trial of high-efficiency particulate air (HEPA) filtration vacuuming showed no effect.⁷ More intensive interventions such as soil lead abatement and paint remediation have not proven effective in good-quality randomized controlled trials.

Increasing dietary calcium and iron and decreasing dietary fat are also commonly recommended for children with elevated blood lead levels, based on animal models and cross-sectional studies. The only randomized controlled trial that investigated calcium supplementation showed no effect on blood lead levels.⁸ Our search revealed no good-quality studies on the effect of iron or fat intake on lead poisoning.

In summary, because the prevalence of lead poisoning varies between communities and continues to change, standard recommendations are not possible. Clinicians must rely on local epidemiologic data to make screening decisions. Although questionnaires are accurate in predicting elevated blood lead levels in some settings, no specific set of questions can be recommended for all populations.

No treatment options for those with mild to moderate elevations in blood lead levels have been shown to improve clinically important outcomes, although some interventions may decrease blood lead levels.

Recommendations from others

The Centers for Disease Control and Prevention (CDC) recommends

• that individual states develop screening plans based on local data
• universal screening at 12 and 24 months of age:

Otherwise screening should be targeted based on a questionnaire on age of housing, recent or ongoing remodeling, and having a sibling or playmate diagnosed with lead poisoning, in addition to questions on locally important risk factors.⁹

The American Academy of Pediatrics endorses the CDC recommendations.² The US Preventive Services Task Force, the American Academy of Family Physicians, and the American College of Preventive Medicine all recommend screening for lead poisoning at 12 months of age in children with demographic or geographic risk factors.^3,10,11

Evidence summary

Nasal congestion is the most common symptom of the common cold, and hundreds of millions of dollars are spent annually on decongestants. A Cochrane review of 4 randomized controlled trials compared single doses of oxymetazoline, pseudoephedrine, and phenylpropanolamine.¹ Included studies involved from 30 to 106 participants, were double-blinded and placebo-controlled, used either topical or oral decongestants for symptoms of less than 5 days’ duration, and measured either subjective or objective relief or adverse events. All 4 studies used nasal airway resistance as an objective measure of nasal congestion, and a combined symptom score as a subjective measure of relief. One study also administered a side-effect questionnaire.

In all studies, topical and oral decongestants were equally efficacious, producing a 13% reduction in subjective symptoms and a significant decrease in nasal airway resistance after 1 dose of decongestant. Only 1 study investigated repeated doses of decongestants and found no significant additional improvement from repeated doses over a 5-day period.

More studies are needed to evaluate efficacy of multiple doses. Clinical interpretation of these results must take into consideration that quality-of-life measures were not evaluated and that none of the studies included children under 12.

Limited data are available on decongestants in sinusitis. Most studies focused on the use of nasal corticosteroids. One placebo-controlled, randomized controlled trial evaluated the effect on mucociliary clearance from adding nasal saline, nasal steroids, or oxymetazoline to antibiotics in acute bacterial sinusitis.² The group using oxymetazoline increased mucociliary clearance immediately (within 20 minutes). However, at 3 weeks, the improvement in mucociliary clearance in the oxymetazoline group was not significantly different than in the other groups.

An additional prospective, placebo-controlled study evaluated improvement in x-ray findings as well as subjective symptoms in acute sinusitis using phenoxymethyl-penicillin (penicillin V) in combination with oxymetazoline or placebo administered via a variety of nasal delivery systems.³ Oxymetazoline was not significantly different from placebo. Controlled prospective studies are lacking to support the use of decongestants in acute sinusitis.

Recommendations from others

Expert opinion from Current Clinical Topics in Infectious Diseases does not recommend the use of decongestants in sinusitis or the common cold in the absence of concurrent allergic rhinosinusitis.⁴ This recommendation is based on the lack of evidence regarding efficacy and the known rebound congestion associated with topical decongestants. If a decongestant is prescribed, the oral route is preferred, with the understanding of potential significant side effects of nervousness, insomnia, tachycardia, and hypertension.

Evidence summary

Nasal congestion is the most common symptom of the common cold, and hundreds of millions of dollars are spent annually on decongestants. A Cochrane review of 4 randomized controlled trials compared single doses of oxymetazoline, pseudoephedrine, and phenylpropanolamine.¹ Included studies involved from 30 to 106 participants, were double-blinded and placebo-controlled, used either topical or oral decongestants for symptoms of less than 5 days’ duration, and measured either subjective or objective relief or adverse events. All 4 studies used nasal airway resistance as an objective measure of nasal congestion, and a combined symptom score as a subjective measure of relief. One study also administered a side-effect questionnaire.

In all studies, topical and oral decongestants were equally efficacious, producing a 13% reduction in subjective symptoms and a significant decrease in nasal airway resistance after 1 dose of decongestant. Only 1 study investigated repeated doses of decongestants and found no significant additional improvement from repeated doses over a 5-day period.

More studies are needed to evaluate efficacy of multiple doses. Clinical interpretation of these results must take into consideration that quality-of-life measures were not evaluated and that none of the studies included children under 12.

Limited data are available on decongestants in sinusitis. Most studies focused on the use of nasal corticosteroids. One placebo-controlled, randomized controlled trial evaluated the effect on mucociliary clearance from adding nasal saline, nasal steroids, or oxymetazoline to antibiotics in acute bacterial sinusitis.² The group using oxymetazoline increased mucociliary clearance immediately (within 20 minutes). However, at 3 weeks, the improvement in mucociliary clearance in the oxymetazoline group was not significantly different than in the other groups.

An additional prospective, placebo-controlled study evaluated improvement in x-ray findings as well as subjective symptoms in acute sinusitis using phenoxymethyl-penicillin (penicillin V) in combination with oxymetazoline or placebo administered via a variety of nasal delivery systems.³ Oxymetazoline was not significantly different from placebo. Controlled prospective studies are lacking to support the use of decongestants in acute sinusitis.

Recommendations from others

Expert opinion from Current Clinical Topics in Infectious Diseases does not recommend the use of decongestants in sinusitis or the common cold in the absence of concurrent allergic rhinosinusitis.⁴ This recommendation is based on the lack of evidence regarding efficacy and the known rebound congestion associated with topical decongestants. If a decongestant is prescribed, the oral route is preferred, with the understanding of potential significant side effects of nervousness, insomnia, tachycardia, and hypertension.

Evidence summary

Nasal congestion is the most common symptom of the common cold, and hundreds of millions of dollars are spent annually on decongestants. A Cochrane review of 4 randomized controlled trials compared single doses of oxymetazoline, pseudoephedrine, and phenylpropanolamine.¹ Included studies involved from 30 to 106 participants, were double-blinded and placebo-controlled, used either topical or oral decongestants for symptoms of less than 5 days’ duration, and measured either subjective or objective relief or adverse events. All 4 studies used nasal airway resistance as an objective measure of nasal congestion, and a combined symptom score as a subjective measure of relief. One study also administered a side-effect questionnaire.

In all studies, topical and oral decongestants were equally efficacious, producing a 13% reduction in subjective symptoms and a significant decrease in nasal airway resistance after 1 dose of decongestant. Only 1 study investigated repeated doses of decongestants and found no significant additional improvement from repeated doses over a 5-day period.

More studies are needed to evaluate efficacy of multiple doses. Clinical interpretation of these results must take into consideration that quality-of-life measures were not evaluated and that none of the studies included children under 12.

Limited data are available on decongestants in sinusitis. Most studies focused on the use of nasal corticosteroids. One placebo-controlled, randomized controlled trial evaluated the effect on mucociliary clearance from adding nasal saline, nasal steroids, or oxymetazoline to antibiotics in acute bacterial sinusitis.² The group using oxymetazoline increased mucociliary clearance immediately (within 20 minutes). However, at 3 weeks, the improvement in mucociliary clearance in the oxymetazoline group was not significantly different than in the other groups.

An additional prospective, placebo-controlled study evaluated improvement in x-ray findings as well as subjective symptoms in acute sinusitis using phenoxymethyl-penicillin (penicillin V) in combination with oxymetazoline or placebo administered via a variety of nasal delivery systems.³ Oxymetazoline was not significantly different from placebo. Controlled prospective studies are lacking to support the use of decongestants in acute sinusitis.

Recommendations from others

Expert opinion from Current Clinical Topics in Infectious Diseases does not recommend the use of decongestants in sinusitis or the common cold in the absence of concurrent allergic rhinosinusitis.⁴ This recommendation is based on the lack of evidence regarding efficacy and the known rebound congestion associated with topical decongestants. If a decongestant is prescribed, the oral route is preferred, with the understanding of potential significant side effects of nervousness, insomnia, tachycardia, and hypertension.

Evidence summary

Antiarrhythmic agents have been studied in patients with heart failure because these persons have a high incidence of sudden death, presumably from ventricular arrhythmias. Although the implantable defibrillator is an alternative antiarrhythmic device that may be preferred for some patients, we restricted our review to pharmacologic antiarrhythmics.

The beta-blockers bisoprolol, carvedilol, and metoprolol^1-3 were studied in large randomized controlled trials. The relative risk reduction (RRR) for sudden death ranged from 10% to 52% in the larger trials and 30% to 39% in meta-analyses.^1-4 The absolute risk reduction (ARR) was about 2% to 3% per year for sudden death and 3% to 5% for total mortality (number needed to treat=20–33 per year).

These beta-blockers were well-tolerated, even in class IV New York Heart Association patients, and improved other endpoints. Although we cannot say whether the benefits are a class effect, they were seen with both beta-1 selective and nonselective agents.

Amiodarone was studied in 2 large randomized controlled trials enrolling patients with heart failure, in trials that included patients with or without heart failure at high risk for sudden death (usually post-myocardial infarction or with complex ventricular arrhythmias), and in meta-analyses.^5-8 The largest randomized controlled trial in heart failure showed a significant ARR of 2.9% for sudden death,⁵ but was unblinded. The largest placebo-controlled trial in heart failure failed to detect a significant decrease in sudden death.⁶

Meta-analyses, weakened by heterogeneity and the inclusion of patients without heart failure, detected a significant 21% to 25% RRR for sudden death,^7,8 and an ARR of 2% to 3% per year. The pooled data from the placebo-controlled heart failure trials showed nonsignificant trends: 1.6% per year ARR for sudden death, 0.6% per year for total mortality.

These possible benefits must be balanced against the risk of harm from amiodarone, including excess rates of pulmonary infiltrate (1.1% per year), thyroid dysfunction (6.8% per year), liver enzyme abnormalities (0.6% per year), neuropathy (0.3% per year), and bradycardia (1.6% per year), as well as a discontinuation rate of 41% compared with 27% for placebo.⁷ No evidence suggested that use of amiodarone in patients with heart failure increased mortality.

Class I antiarrhythmics and other class III agents have not been studied in heart failure trials, but were associated with increased mortality in studies of patients at high risk for ventricular arrhythmia,^9,10 including patients with left ventricular dysfunction. Because this increase in mortality is thought to be due to proarrhythmic properties of the drugs, further trials in heart failure patients are unlikely to occur.

Recommendations from others

American College of Cardiology/American Heart Association (ACC/AHA),¹¹ European Society of Cardiology (ESC),¹² and Heart Failure Society of America (HFSA) guidelines¹³ address heart failure. ACC/AHA and ESC reports specifically mention that beta-blockers reduce sudden death. Both strongly support the use of beta-blockers in patients with heart failure.

ACC/AHA finds “conflicting evidence and/or a divergence of opinion about the usefulness/ efficacy” of amiodarone to prevent sudden death and advises: “routine use of amiodarone to prevent sudden death is not recommended.” The ESC and HFSA also recommend against routine use of amiodarone.

All 3 guidelines, however, state that for the control of symptomatic arrhythmias in heart failure, amiodarone is the antiarrhythmic agent of choice. All 3 also recommend not using class I or other class III agents in heart failure.

Evidence summary

Antiarrhythmic agents have been studied in patients with heart failure because these persons have a high incidence of sudden death, presumably from ventricular arrhythmias. Although the implantable defibrillator is an alternative antiarrhythmic device that may be preferred for some patients, we restricted our review to pharmacologic antiarrhythmics.

The beta-blockers bisoprolol, carvedilol, and metoprolol^1-3 were studied in large randomized controlled trials. The relative risk reduction (RRR) for sudden death ranged from 10% to 52% in the larger trials and 30% to 39% in meta-analyses.^1-4 The absolute risk reduction (ARR) was about 2% to 3% per year for sudden death and 3% to 5% for total mortality (number needed to treat=20–33 per year).

These beta-blockers were well-tolerated, even in class IV New York Heart Association patients, and improved other endpoints. Although we cannot say whether the benefits are a class effect, they were seen with both beta-1 selective and nonselective agents.

Amiodarone was studied in 2 large randomized controlled trials enrolling patients with heart failure, in trials that included patients with or without heart failure at high risk for sudden death (usually post-myocardial infarction or with complex ventricular arrhythmias), and in meta-analyses.^5-8 The largest randomized controlled trial in heart failure showed a significant ARR of 2.9% for sudden death,⁵ but was unblinded. The largest placebo-controlled trial in heart failure failed to detect a significant decrease in sudden death.⁶

Meta-analyses, weakened by heterogeneity and the inclusion of patients without heart failure, detected a significant 21% to 25% RRR for sudden death,^7,8 and an ARR of 2% to 3% per year. The pooled data from the placebo-controlled heart failure trials showed nonsignificant trends: 1.6% per year ARR for sudden death, 0.6% per year for total mortality.

These possible benefits must be balanced against the risk of harm from amiodarone, including excess rates of pulmonary infiltrate (1.1% per year), thyroid dysfunction (6.8% per year), liver enzyme abnormalities (0.6% per year), neuropathy (0.3% per year), and bradycardia (1.6% per year), as well as a discontinuation rate of 41% compared with 27% for placebo.⁷ No evidence suggested that use of amiodarone in patients with heart failure increased mortality.

Class I antiarrhythmics and other class III agents have not been studied in heart failure trials, but were associated with increased mortality in studies of patients at high risk for ventricular arrhythmia,^9,10 including patients with left ventricular dysfunction. Because this increase in mortality is thought to be due to proarrhythmic properties of the drugs, further trials in heart failure patients are unlikely to occur.

Recommendations from others

American College of Cardiology/American Heart Association (ACC/AHA),¹¹ European Society of Cardiology (ESC),¹² and Heart Failure Society of America (HFSA) guidelines¹³ address heart failure. ACC/AHA and ESC reports specifically mention that beta-blockers reduce sudden death. Both strongly support the use of beta-blockers in patients with heart failure.

ACC/AHA finds “conflicting evidence and/or a divergence of opinion about the usefulness/ efficacy” of amiodarone to prevent sudden death and advises: “routine use of amiodarone to prevent sudden death is not recommended.” The ESC and HFSA also recommend against routine use of amiodarone.

All 3 guidelines, however, state that for the control of symptomatic arrhythmias in heart failure, amiodarone is the antiarrhythmic agent of choice. All 3 also recommend not using class I or other class III agents in heart failure.

Evidence summary

Antiarrhythmic agents have been studied in patients with heart failure because these persons have a high incidence of sudden death, presumably from ventricular arrhythmias. Although the implantable defibrillator is an alternative antiarrhythmic device that may be preferred for some patients, we restricted our review to pharmacologic antiarrhythmics.

The beta-blockers bisoprolol, carvedilol, and metoprolol^1-3 were studied in large randomized controlled trials. The relative risk reduction (RRR) for sudden death ranged from 10% to 52% in the larger trials and 30% to 39% in meta-analyses.^1-4 The absolute risk reduction (ARR) was about 2% to 3% per year for sudden death and 3% to 5% for total mortality (number needed to treat=20–33 per year).

These beta-blockers were well-tolerated, even in class IV New York Heart Association patients, and improved other endpoints. Although we cannot say whether the benefits are a class effect, they were seen with both beta-1 selective and nonselective agents.

Amiodarone was studied in 2 large randomized controlled trials enrolling patients with heart failure, in trials that included patients with or without heart failure at high risk for sudden death (usually post-myocardial infarction or with complex ventricular arrhythmias), and in meta-analyses.^5-8 The largest randomized controlled trial in heart failure showed a significant ARR of 2.9% for sudden death,⁵ but was unblinded. The largest placebo-controlled trial in heart failure failed to detect a significant decrease in sudden death.⁶

Meta-analyses, weakened by heterogeneity and the inclusion of patients without heart failure, detected a significant 21% to 25% RRR for sudden death,^7,8 and an ARR of 2% to 3% per year. The pooled data from the placebo-controlled heart failure trials showed nonsignificant trends: 1.6% per year ARR for sudden death, 0.6% per year for total mortality.

These possible benefits must be balanced against the risk of harm from amiodarone, including excess rates of pulmonary infiltrate (1.1% per year), thyroid dysfunction (6.8% per year), liver enzyme abnormalities (0.6% per year), neuropathy (0.3% per year), and bradycardia (1.6% per year), as well as a discontinuation rate of 41% compared with 27% for placebo.⁷ No evidence suggested that use of amiodarone in patients with heart failure increased mortality.

Class I antiarrhythmics and other class III agents have not been studied in heart failure trials, but were associated with increased mortality in studies of patients at high risk for ventricular arrhythmia,^9,10 including patients with left ventricular dysfunction. Because this increase in mortality is thought to be due to proarrhythmic properties of the drugs, further trials in heart failure patients are unlikely to occur.

Recommendations from others

American College of Cardiology/American Heart Association (ACC/AHA),¹¹ European Society of Cardiology (ESC),¹² and Heart Failure Society of America (HFSA) guidelines¹³ address heart failure. ACC/AHA and ESC reports specifically mention that beta-blockers reduce sudden death. Both strongly support the use of beta-blockers in patients with heart failure.

ACC/AHA finds “conflicting evidence and/or a divergence of opinion about the usefulness/ efficacy” of amiodarone to prevent sudden death and advises: “routine use of amiodarone to prevent sudden death is not recommended.” The ESC and HFSA also recommend against routine use of amiodarone.

All 3 guidelines, however, state that for the control of symptomatic arrhythmias in heart failure, amiodarone is the antiarrhythmic agent of choice. All 3 also recommend not using class I or other class III agents in heart failure.

Evidence summary

The goal of physical therapy is to maximize function and reduce impairment to limit disability in patients with musculoskeletal conditions.¹ Based on a British study, physical therapists most commonly use exercise, education about correct posture and functional activity, relaxation, and energy conservation and fatigue management.² For this review, physical therapy is defined as a treatment program that includes patient education and supervised exercise.

In the highest-quality trial, Buckelew and colleagues³ randomized 119 subjects to 1 of 4 groups: biofeedback and relaxation training, exercise training, combination treatment, and an education and attention control program. Individuals were evaluated on measures of pain, function, disease impact, and self-efficacy. Evaluators were blinded to treatment group. Patients were followed for 2 years, and follow-up information was available on 85% of patients.

At immediate postintervention follow-up, all treatment groups were significantly improved on tender-point index score compared with the control group, but this was due to a modest deterioration for the control group rather than improvements in the treatment groups. In addition, all groups showed improvements in self-efficacy for function compared with the control group but not for other self-efficacy measures. While within-group improvements in the treatment groups were seen, no significant differences were seen from the control group.

Another trial randomized 99 patients to 3 groups: education and cognitive behavioral therapy; education, cognitive behavioral therapy and exercise; or a wait-list control group.⁴ At the 6-month follow-up, the education group scored significantly higher than the others—but only on self-reported measures of daily functioning and self-efficacy.

In another study, 45 patients with fibromyalgia were randomly assigned to a 6-week program combining exercise and multidisciplinary education or to a control group.⁵ The treatment group had significant improvements in walking distance and for 2 measures on the Fibromyalgia Impact Questionnaire (feeling bad and morning fatigue). Keel and colleagues⁶ found no immediate treatment benefit following 15 weeks of education, cognitive behavioral therapy, and exercise vs relaxation training in their small randomized controlled trial.⁶

In contrast, another study reported significant and immediate improvements in 2 groups— exercise and education; exercise, education, and cognitive behavioral therapy—when compared with control patients on self-reported symptoms and knowledge.^# The exercise and education group was also better than the control patients in self-reported daily functioning.

We identified 2 additional trials examining different types of physical therapy for fibromyalgia that did not include control groups. In a trial of muscle strengthening vs flexibility training, investigators found no difference between groups on measures including tender points and disease and symptom severity.⁸ They did find benefits in symptoms and self-efficacy over baseline, but it is not known whether these were sustained.

In a trial comparing 2 physical therapies— body awareness therapy and the Mensendieck system—Kendall and colleagues⁹ found greater improvements at 18-month follow-up in the Mensendieck group.⁹ Benefits were seen on the Fibromyalgia Impact Questionnaire, self-efficacy measures, and pain at worst site. The Mensendieck system uses individual interview, analysis of movement patterns, a discussion of possible corrections followed by practice, and relaxation exercises.

Multidisciplinary rehabilitation, often including physical therapy, has also been studied in a limited way. In a systematic review of 7 studies fulfilling inclusion criteria (a total of 1050 patients), Karjalainen and colleagues¹⁰ concluded that although education combined with physical training seemed to have some positive results at long-term follow-up, the level of scientific evidence required for recommending these programs for fibromyalgia was lacking.¹⁰

Because exercise is believed to be an essential component of physical therapy, we examined the results of a systematic review of exercise for treating fibromyalgia. The authors found 7 high-quality studies, 4 of aerobic training, and concluded that supervised aerobic exercise training had beneficial effects on physical capacity, tender-point threshold, and pain.¹¹ Other investigators have questioned the usefulness of aerobic exercise because long-term benefit remains unclear and compliance is poor.

Recommendations from others

We were unable to find any guidelines for the treatment of fibromyalgia. Patient information sheets from both the American College of Rheumatology (www.rheumatology.org) and American Academy of Orthopaedic Surgeons (orthoinfo.aaos.org) recommend physical modalities such as heat application, massage, and exercise, including fitness training.

Authors of chapters on fibromyalgia in both Kelly’s Textbook of Rheumatology and Harrison’s Principles of Internal Medicine suggest that patients may benefit from regular low-impact aerobic exercise.^12,13

Evidence summary

The goal of physical therapy is to maximize function and reduce impairment to limit disability in patients with musculoskeletal conditions.¹ Based on a British study, physical therapists most commonly use exercise, education about correct posture and functional activity, relaxation, and energy conservation and fatigue management.² For this review, physical therapy is defined as a treatment program that includes patient education and supervised exercise.

In the highest-quality trial, Buckelew and colleagues³ randomized 119 subjects to 1 of 4 groups: biofeedback and relaxation training, exercise training, combination treatment, and an education and attention control program. Individuals were evaluated on measures of pain, function, disease impact, and self-efficacy. Evaluators were blinded to treatment group. Patients were followed for 2 years, and follow-up information was available on 85% of patients.

At immediate postintervention follow-up, all treatment groups were significantly improved on tender-point index score compared with the control group, but this was due to a modest deterioration for the control group rather than improvements in the treatment groups. In addition, all groups showed improvements in self-efficacy for function compared with the control group but not for other self-efficacy measures. While within-group improvements in the treatment groups were seen, no significant differences were seen from the control group.

Another trial randomized 99 patients to 3 groups: education and cognitive behavioral therapy; education, cognitive behavioral therapy and exercise; or a wait-list control group.⁴ At the 6-month follow-up, the education group scored significantly higher than the others—but only on self-reported measures of daily functioning and self-efficacy.

In another study, 45 patients with fibromyalgia were randomly assigned to a 6-week program combining exercise and multidisciplinary education or to a control group.⁵ The treatment group had significant improvements in walking distance and for 2 measures on the Fibromyalgia Impact Questionnaire (feeling bad and morning fatigue). Keel and colleagues⁶ found no immediate treatment benefit following 15 weeks of education, cognitive behavioral therapy, and exercise vs relaxation training in their small randomized controlled trial.⁶

In contrast, another study reported significant and immediate improvements in 2 groups— exercise and education; exercise, education, and cognitive behavioral therapy—when compared with control patients on self-reported symptoms and knowledge.^# The exercise and education group was also better than the control patients in self-reported daily functioning.

We identified 2 additional trials examining different types of physical therapy for fibromyalgia that did not include control groups. In a trial of muscle strengthening vs flexibility training, investigators found no difference between groups on measures including tender points and disease and symptom severity.⁸ They did find benefits in symptoms and self-efficacy over baseline, but it is not known whether these were sustained.

In a trial comparing 2 physical therapies— body awareness therapy and the Mensendieck system—Kendall and colleagues⁹ found greater improvements at 18-month follow-up in the Mensendieck group.⁹ Benefits were seen on the Fibromyalgia Impact Questionnaire, self-efficacy measures, and pain at worst site. The Mensendieck system uses individual interview, analysis of movement patterns, a discussion of possible corrections followed by practice, and relaxation exercises.

Multidisciplinary rehabilitation, often including physical therapy, has also been studied in a limited way. In a systematic review of 7 studies fulfilling inclusion criteria (a total of 1050 patients), Karjalainen and colleagues¹⁰ concluded that although education combined with physical training seemed to have some positive results at long-term follow-up, the level of scientific evidence required for recommending these programs for fibromyalgia was lacking.¹⁰

Because exercise is believed to be an essential component of physical therapy, we examined the results of a systematic review of exercise for treating fibromyalgia. The authors found 7 high-quality studies, 4 of aerobic training, and concluded that supervised aerobic exercise training had beneficial effects on physical capacity, tender-point threshold, and pain.¹¹ Other investigators have questioned the usefulness of aerobic exercise because long-term benefit remains unclear and compliance is poor.

Recommendations from others

We were unable to find any guidelines for the treatment of fibromyalgia. Patient information sheets from both the American College of Rheumatology (www.rheumatology.org) and American Academy of Orthopaedic Surgeons (orthoinfo.aaos.org) recommend physical modalities such as heat application, massage, and exercise, including fitness training.

Authors of chapters on fibromyalgia in both Kelly’s Textbook of Rheumatology and Harrison’s Principles of Internal Medicine suggest that patients may benefit from regular low-impact aerobic exercise.^12,13

Evidence summary

The goal of physical therapy is to maximize function and reduce impairment to limit disability in patients with musculoskeletal conditions.¹ Based on a British study, physical therapists most commonly use exercise, education about correct posture and functional activity, relaxation, and energy conservation and fatigue management.² For this review, physical therapy is defined as a treatment program that includes patient education and supervised exercise.

In the highest-quality trial, Buckelew and colleagues³ randomized 119 subjects to 1 of 4 groups: biofeedback and relaxation training, exercise training, combination treatment, and an education and attention control program. Individuals were evaluated on measures of pain, function, disease impact, and self-efficacy. Evaluators were blinded to treatment group. Patients were followed for 2 years, and follow-up information was available on 85% of patients.

At immediate postintervention follow-up, all treatment groups were significantly improved on tender-point index score compared with the control group, but this was due to a modest deterioration for the control group rather than improvements in the treatment groups. In addition, all groups showed improvements in self-efficacy for function compared with the control group but not for other self-efficacy measures. While within-group improvements in the treatment groups were seen, no significant differences were seen from the control group.

Another trial randomized 99 patients to 3 groups: education and cognitive behavioral therapy; education, cognitive behavioral therapy and exercise; or a wait-list control group.⁴ At the 6-month follow-up, the education group scored significantly higher than the others—but only on self-reported measures of daily functioning and self-efficacy.

In another study, 45 patients with fibromyalgia were randomly assigned to a 6-week program combining exercise and multidisciplinary education or to a control group.⁵ The treatment group had significant improvements in walking distance and for 2 measures on the Fibromyalgia Impact Questionnaire (feeling bad and morning fatigue). Keel and colleagues⁶ found no immediate treatment benefit following 15 weeks of education, cognitive behavioral therapy, and exercise vs relaxation training in their small randomized controlled trial.⁶

In contrast, another study reported significant and immediate improvements in 2 groups— exercise and education; exercise, education, and cognitive behavioral therapy—when compared with control patients on self-reported symptoms and knowledge.^# The exercise and education group was also better than the control patients in self-reported daily functioning.

We identified 2 additional trials examining different types of physical therapy for fibromyalgia that did not include control groups. In a trial of muscle strengthening vs flexibility training, investigators found no difference between groups on measures including tender points and disease and symptom severity.⁸ They did find benefits in symptoms and self-efficacy over baseline, but it is not known whether these were sustained.

In a trial comparing 2 physical therapies— body awareness therapy and the Mensendieck system—Kendall and colleagues⁹ found greater improvements at 18-month follow-up in the Mensendieck group.⁹ Benefits were seen on the Fibromyalgia Impact Questionnaire, self-efficacy measures, and pain at worst site. The Mensendieck system uses individual interview, analysis of movement patterns, a discussion of possible corrections followed by practice, and relaxation exercises.

Multidisciplinary rehabilitation, often including physical therapy, has also been studied in a limited way. In a systematic review of 7 studies fulfilling inclusion criteria (a total of 1050 patients), Karjalainen and colleagues¹⁰ concluded that although education combined with physical training seemed to have some positive results at long-term follow-up, the level of scientific evidence required for recommending these programs for fibromyalgia was lacking.¹⁰

Because exercise is believed to be an essential component of physical therapy, we examined the results of a systematic review of exercise for treating fibromyalgia. The authors found 7 high-quality studies, 4 of aerobic training, and concluded that supervised aerobic exercise training had beneficial effects on physical capacity, tender-point threshold, and pain.¹¹ Other investigators have questioned the usefulness of aerobic exercise because long-term benefit remains unclear and compliance is poor.

Recommendations from others

We were unable to find any guidelines for the treatment of fibromyalgia. Patient information sheets from both the American College of Rheumatology (www.rheumatology.org) and American Academy of Orthopaedic Surgeons (orthoinfo.aaos.org) recommend physical modalities such as heat application, massage, and exercise, including fitness training.

Authors of chapters on fibromyalgia in both Kelly’s Textbook of Rheumatology and Harrison’s Principles of Internal Medicine suggest that patients may benefit from regular low-impact aerobic exercise.^12,13

Evidence summary

In a prospective, observer-blinded study, 103 subjects were randomized to 1 of 3 treatment categories: anti-inflammatory (etodolac plus corticosteroid injections); accommodative (viscoelastic heel cup); or mechanical (low-dye tapping for 1 month followed by rigid custom orthosis for 2 months).¹ After 3 months of treatment, 70% of patients in the mechanical treatment group rated their functional outcome as excellent, compared with only 33% of the anti-inflammatory group and 30% of the accommodative group (P=.005). Additionally, the mechanically treated group was less likely to terminate treatment early because of treatment failure (P<.001).

Several of the same researchers then went a step further to find out which specific mechanical treatment is best. They found no statistically significant difference among treatment with tension night splinting ( Figure 1 ), custom rigid orthosis, and over-the-counter arch supports.² A retrospective study of 237 subjects also concluded that mechanical treatment is better than anti-inflammatory or accommodative treatments.³

Another prospective, observer-blinded study randomized 116 patients to 1 of 2 groups for 3 months.⁴ The first group of patients were treated with a nonsteroidal anti-inflammatory drug (piroxicam) and Achilles tendon stretching 3 times a day. The second group received the same treatment but also wore plastic tension night splints in 5° of dorsiflexion. After 3 months, in an intention-to-treat analysis, no statistically significant difference was detected in subjective pain between the 2 groups. In this study, patient compliance with the tension night splinting was poor, and this likely affected the outcome.

From 1993–1995 an observer-blinded randomized controlled trial of 112 patients compared standard with sham extracorporeal shock wave therapy.⁵ The main outcome measure was patient satisfaction on a 4-step score at 6 months and 5 years. At 6 months, the treatment group had a significantly better 4-step score than the placebo group (P<.0001). In fact, 51% of treatment-group patients were pain-free, while none of the 48 placebo-group patients were painfree. After 5 years, the 4-step score only demonstrated a trend in favor of the treatment group (P<.071) because of a high rate of good results from subsequent surgery in the placebo group. Thirteen percent of the treatment-group patients had undergone a heel operation, compared with 58% of placebo-group patients.

A controlled and observer-blinded study of 302 patients with plantar fasciitis compared standard extracorporeal shock wave therapy with sham treatment.⁶ The treated patients had significantly lower pain scores (as measured on a visual analog scale) than the placebo group (1.9 vs 4.7). Three months post-treatment, half as many treated patients were taking pain medication when compared with placebo patients. After 1 year of follow-up, 94% of the treatment group patients were still pain-free, with a pain score of <2.

One randomized controlled study of 166 patients found no evidence to support a beneficial effect on pain, function, and quality of life of extracorporeal shock wave therapy over a sham treatment.⁷ Of note, this study enrolled patients who had a minimum of 6 weeks of symptoms. All recommendations in the US are to reserve extracorporeal shock wave therapy for patients with more than 6 months of symptoms.

A meta-analysis of 8 published studies involving 840 patients whose condition was not improved after conservative therapy for at least 6 months showed that up to 88% of patients experienced good to excellent outcomes with extracorporeal shock wave therapy and were satisfied with the result. ⁶

As for surgical treatment, in a prospective study of 43 patients with 47 painful heels followed for an average of 31 months, only 49% of the patients were satisfied with their outcome.⁸ Patient expectations should be considered in preoperative counseling. In contrast to surgery, either open or endoscopic, extracorporeal shock wave therapy does not require the patient avoid weightbearing or a prolonged time for return to work.

FIGURE 1
Tension night splinting

Recommendations from others

Figure 2 has been modified from a clinical practice guideline on the treatment of plantar fasciitis published by the American College of Foot and Ankle Surgeons.⁹

FIGURE 2
Treatment of plantar fasciitis

Evidence summary

In a prospective, observer-blinded study, 103 subjects were randomized to 1 of 3 treatment categories: anti-inflammatory (etodolac plus corticosteroid injections); accommodative (viscoelastic heel cup); or mechanical (low-dye tapping for 1 month followed by rigid custom orthosis for 2 months).¹ After 3 months of treatment, 70% of patients in the mechanical treatment group rated their functional outcome as excellent, compared with only 33% of the anti-inflammatory group and 30% of the accommodative group (P=.005). Additionally, the mechanically treated group was less likely to terminate treatment early because of treatment failure (P<.001).

Several of the same researchers then went a step further to find out which specific mechanical treatment is best. They found no statistically significant difference among treatment with tension night splinting ( Figure 1 ), custom rigid orthosis, and over-the-counter arch supports.² A retrospective study of 237 subjects also concluded that mechanical treatment is better than anti-inflammatory or accommodative treatments.³

Another prospective, observer-blinded study randomized 116 patients to 1 of 2 groups for 3 months.⁴ The first group of patients were treated with a nonsteroidal anti-inflammatory drug (piroxicam) and Achilles tendon stretching 3 times a day. The second group received the same treatment but also wore plastic tension night splints in 5° of dorsiflexion. After 3 months, in an intention-to-treat analysis, no statistically significant difference was detected in subjective pain between the 2 groups. In this study, patient compliance with the tension night splinting was poor, and this likely affected the outcome.

From 1993–1995 an observer-blinded randomized controlled trial of 112 patients compared standard with sham extracorporeal shock wave therapy.⁵ The main outcome measure was patient satisfaction on a 4-step score at 6 months and 5 years. At 6 months, the treatment group had a significantly better 4-step score than the placebo group (P<.0001). In fact, 51% of treatment-group patients were pain-free, while none of the 48 placebo-group patients were painfree. After 5 years, the 4-step score only demonstrated a trend in favor of the treatment group (P<.071) because of a high rate of good results from subsequent surgery in the placebo group. Thirteen percent of the treatment-group patients had undergone a heel operation, compared with 58% of placebo-group patients.

A controlled and observer-blinded study of 302 patients with plantar fasciitis compared standard extracorporeal shock wave therapy with sham treatment.⁶ The treated patients had significantly lower pain scores (as measured on a visual analog scale) than the placebo group (1.9 vs 4.7). Three months post-treatment, half as many treated patients were taking pain medication when compared with placebo patients. After 1 year of follow-up, 94% of the treatment group patients were still pain-free, with a pain score of <2.

One randomized controlled study of 166 patients found no evidence to support a beneficial effect on pain, function, and quality of life of extracorporeal shock wave therapy over a sham treatment.⁷ Of note, this study enrolled patients who had a minimum of 6 weeks of symptoms. All recommendations in the US are to reserve extracorporeal shock wave therapy for patients with more than 6 months of symptoms.

A meta-analysis of 8 published studies involving 840 patients whose condition was not improved after conservative therapy for at least 6 months showed that up to 88% of patients experienced good to excellent outcomes with extracorporeal shock wave therapy and were satisfied with the result. ⁶

As for surgical treatment, in a prospective study of 43 patients with 47 painful heels followed for an average of 31 months, only 49% of the patients were satisfied with their outcome.⁸ Patient expectations should be considered in preoperative counseling. In contrast to surgery, either open or endoscopic, extracorporeal shock wave therapy does not require the patient avoid weightbearing or a prolonged time for return to work.

FIGURE 1
Tension night splinting

Recommendations from others

Figure 2 has been modified from a clinical practice guideline on the treatment of plantar fasciitis published by the American College of Foot and Ankle Surgeons.⁹

FIGURE 2
Treatment of plantar fasciitis

Evidence summary

In a prospective, observer-blinded study, 103 subjects were randomized to 1 of 3 treatment categories: anti-inflammatory (etodolac plus corticosteroid injections); accommodative (viscoelastic heel cup); or mechanical (low-dye tapping for 1 month followed by rigid custom orthosis for 2 months).¹ After 3 months of treatment, 70% of patients in the mechanical treatment group rated their functional outcome as excellent, compared with only 33% of the anti-inflammatory group and 30% of the accommodative group (P=.005). Additionally, the mechanically treated group was less likely to terminate treatment early because of treatment failure (P<.001).

Several of the same researchers then went a step further to find out which specific mechanical treatment is best. They found no statistically significant difference among treatment with tension night splinting ( Figure 1 ), custom rigid orthosis, and over-the-counter arch supports.² A retrospective study of 237 subjects also concluded that mechanical treatment is better than anti-inflammatory or accommodative treatments.³

Another prospective, observer-blinded study randomized 116 patients to 1 of 2 groups for 3 months.⁴ The first group of patients were treated with a nonsteroidal anti-inflammatory drug (piroxicam) and Achilles tendon stretching 3 times a day. The second group received the same treatment but also wore plastic tension night splints in 5° of dorsiflexion. After 3 months, in an intention-to-treat analysis, no statistically significant difference was detected in subjective pain between the 2 groups. In this study, patient compliance with the tension night splinting was poor, and this likely affected the outcome.

From 1993–1995 an observer-blinded randomized controlled trial of 112 patients compared standard with sham extracorporeal shock wave therapy.⁵ The main outcome measure was patient satisfaction on a 4-step score at 6 months and 5 years. At 6 months, the treatment group had a significantly better 4-step score than the placebo group (P<.0001). In fact, 51% of treatment-group patients were pain-free, while none of the 48 placebo-group patients were painfree. After 5 years, the 4-step score only demonstrated a trend in favor of the treatment group (P<.071) because of a high rate of good results from subsequent surgery in the placebo group. Thirteen percent of the treatment-group patients had undergone a heel operation, compared with 58% of placebo-group patients.

A controlled and observer-blinded study of 302 patients with plantar fasciitis compared standard extracorporeal shock wave therapy with sham treatment.⁶ The treated patients had significantly lower pain scores (as measured on a visual analog scale) than the placebo group (1.9 vs 4.7). Three months post-treatment, half as many treated patients were taking pain medication when compared with placebo patients. After 1 year of follow-up, 94% of the treatment group patients were still pain-free, with a pain score of <2.

One randomized controlled study of 166 patients found no evidence to support a beneficial effect on pain, function, and quality of life of extracorporeal shock wave therapy over a sham treatment.⁷ Of note, this study enrolled patients who had a minimum of 6 weeks of symptoms. All recommendations in the US are to reserve extracorporeal shock wave therapy for patients with more than 6 months of symptoms.

A meta-analysis of 8 published studies involving 840 patients whose condition was not improved after conservative therapy for at least 6 months showed that up to 88% of patients experienced good to excellent outcomes with extracorporeal shock wave therapy and were satisfied with the result. ⁶

As for surgical treatment, in a prospective study of 43 patients with 47 painful heels followed for an average of 31 months, only 49% of the patients were satisfied with their outcome.⁸ Patient expectations should be considered in preoperative counseling. In contrast to surgery, either open or endoscopic, extracorporeal shock wave therapy does not require the patient avoid weightbearing or a prolonged time for return to work.

FIGURE 1
Tension night splinting

Recommendations from others

Figure 2 has been modified from a clinical practice guideline on the treatment of plantar fasciitis published by the American College of Foot and Ankle Surgeons.⁹

FIGURE 2
Treatment of plantar fasciitis

Evidence summary

OME is diagnosed by visualization of an effusion on otoscopy, by limited tympanic membrane movement on insufflation, or by abnormal tympanometry, all in the absence of acute inflammation. OME is defined as chronic when the effusion has been present for at least 3 months.

The natural course of OME was observed in a longitudinal cohort study of 1439 children aged 2 years in the Netherlands. Single or recurrent flat screening tympanograms were noted in 20% and remitted spontaneously at a rate of 50% every 3 months.¹ This prevalence and spontaneous resolution rate is consistent with other studies.

Three randomized controlled trials published in English tested intranasal steroids for OME (Table).

The Lilholdt study enrolled children through a private ear, nose, and throat clinic over autumn, winter, and spring with a primary or new bout of OME.

The Shapiro study enrolled children who had documented allergic rhinitis and OME with failure to respond to 4 weeks of oral antihistamine and decongestant therapy at time of entry. This was the only study with short-term follow-up comparing intranasal steroids with control. The odds ratio for OME persisting after 3 weeks was 2.12 (95% confidence interval [CI], 0.65-6.90).³

The Tracy study enrolled children with chronic OME referred to a chronic ear clinic from October to June. Inclusion criteria included 3 episodes of acute otitis media in the prior 6 months or 4 episodes in the prior 12 months. This was a randomized comparison study with 3 treatment arms: an active nasal spray group and 2 control groups. The odds ratio for OME persisting after short-term follow-up was 0.79 (95% CI, 0.20-3.19); after intermediate follow-up the odds ratio was 0.72 (95% CI, 0.21-2.44).

This study, which included a symptom score after 3 months, favored treatment, with a weighted mean difference of -4.5, but with wide 95% CI of -10.28 to 1.28. An effect was demonstrated on clearing effusions in the short term, but the advantage appeared to vanish for the most part by 3 months. The study did not evaluate improvements in hearing.⁴

No adverse effects of intranasal steroid treatment were seen except for transient drops in cortisol levels in the Shapiro study, which tested dexamethasone. Approximately 8 randomized controlled trials using oral steroids with and without antibiotics for OME and chronic OME mirror a trend for short-term benefit of treatment, spontaneous resolution, and frequent recurrence.

In summary, limited evidence exists for short-term improvement of OME with intranasal steroids plus antibiotics, and no evidence exists for lasting beneficial effect on effusion or OME associated hearing loss.

TABLE
Clinical trials: Intranasal steroids for otitis media with effusion

Recommendations from others

The Canadian Task Force on Preventative Health Care found insufficient evidence to recommend screening for OME to prevent delayed language development.⁵

The Cochrane Ear, Nose and Throat Disorders Group concludes that both oral and topical intranasal steroids alone or in combination with an antibiotic lead to a quicker resolution of OME in the short term, but no long-term benefit is seen from treating OME effusions or associated hearing loss with topical intranasal steroids.⁶ They separately reviewed antibiotic treatment for OME, noting the short-term benefit above, but cited several drawbacks including cost and increased antibacterial resistance.⁷

The American Academy of Family Physicians Clinical Recommendation on Otitis Media with Effusion in Young Children does not recommend steroid medications for treatment of OME in a child of any age.⁸

ACKNOWLEDGMENTS

Thanks to Marianne Broers, MD for her translation of reference 1 from Dutch.

Evidence summary

OME is diagnosed by visualization of an effusion on otoscopy, by limited tympanic membrane movement on insufflation, or by abnormal tympanometry, all in the absence of acute inflammation. OME is defined as chronic when the effusion has been present for at least 3 months.

The natural course of OME was observed in a longitudinal cohort study of 1439 children aged 2 years in the Netherlands. Single or recurrent flat screening tympanograms were noted in 20% and remitted spontaneously at a rate of 50% every 3 months.¹ This prevalence and spontaneous resolution rate is consistent with other studies.

Three randomized controlled trials published in English tested intranasal steroids for OME (Table).

The Lilholdt study enrolled children through a private ear, nose, and throat clinic over autumn, winter, and spring with a primary or new bout of OME.

The Shapiro study enrolled children who had documented allergic rhinitis and OME with failure to respond to 4 weeks of oral antihistamine and decongestant therapy at time of entry. This was the only study with short-term follow-up comparing intranasal steroids with control. The odds ratio for OME persisting after 3 weeks was 2.12 (95% confidence interval [CI], 0.65-6.90).³

The Tracy study enrolled children with chronic OME referred to a chronic ear clinic from October to June. Inclusion criteria included 3 episodes of acute otitis media in the prior 6 months or 4 episodes in the prior 12 months. This was a randomized comparison study with 3 treatment arms: an active nasal spray group and 2 control groups. The odds ratio for OME persisting after short-term follow-up was 0.79 (95% CI, 0.20-3.19); after intermediate follow-up the odds ratio was 0.72 (95% CI, 0.21-2.44).

This study, which included a symptom score after 3 months, favored treatment, with a weighted mean difference of -4.5, but with wide 95% CI of -10.28 to 1.28. An effect was demonstrated on clearing effusions in the short term, but the advantage appeared to vanish for the most part by 3 months. The study did not evaluate improvements in hearing.⁴

No adverse effects of intranasal steroid treatment were seen except for transient drops in cortisol levels in the Shapiro study, which tested dexamethasone. Approximately 8 randomized controlled trials using oral steroids with and without antibiotics for OME and chronic OME mirror a trend for short-term benefit of treatment, spontaneous resolution, and frequent recurrence.

In summary, limited evidence exists for short-term improvement of OME with intranasal steroids plus antibiotics, and no evidence exists for lasting beneficial effect on effusion or OME associated hearing loss.

TABLE
Clinical trials: Intranasal steroids for otitis media with effusion

Recommendations from others

The Canadian Task Force on Preventative Health Care found insufficient evidence to recommend screening for OME to prevent delayed language development.⁵

The Cochrane Ear, Nose and Throat Disorders Group concludes that both oral and topical intranasal steroids alone or in combination with an antibiotic lead to a quicker resolution of OME in the short term, but no long-term benefit is seen from treating OME effusions or associated hearing loss with topical intranasal steroids.⁶ They separately reviewed antibiotic treatment for OME, noting the short-term benefit above, but cited several drawbacks including cost and increased antibacterial resistance.⁷

The American Academy of Family Physicians Clinical Recommendation on Otitis Media with Effusion in Young Children does not recommend steroid medications for treatment of OME in a child of any age.⁸

ACKNOWLEDGMENTS

Thanks to Marianne Broers, MD for her translation of reference 1 from Dutch.

Evidence summary

OME is diagnosed by visualization of an effusion on otoscopy, by limited tympanic membrane movement on insufflation, or by abnormal tympanometry, all in the absence of acute inflammation. OME is defined as chronic when the effusion has been present for at least 3 months.

The natural course of OME was observed in a longitudinal cohort study of 1439 children aged 2 years in the Netherlands. Single or recurrent flat screening tympanograms were noted in 20% and remitted spontaneously at a rate of 50% every 3 months.¹ This prevalence and spontaneous resolution rate is consistent with other studies.

Three randomized controlled trials published in English tested intranasal steroids for OME (Table).

The Lilholdt study enrolled children through a private ear, nose, and throat clinic over autumn, winter, and spring with a primary or new bout of OME.

The Shapiro study enrolled children who had documented allergic rhinitis and OME with failure to respond to 4 weeks of oral antihistamine and decongestant therapy at time of entry. This was the only study with short-term follow-up comparing intranasal steroids with control. The odds ratio for OME persisting after 3 weeks was 2.12 (95% confidence interval [CI], 0.65-6.90).³

The Tracy study enrolled children with chronic OME referred to a chronic ear clinic from October to June. Inclusion criteria included 3 episodes of acute otitis media in the prior 6 months or 4 episodes in the prior 12 months. This was a randomized comparison study with 3 treatment arms: an active nasal spray group and 2 control groups. The odds ratio for OME persisting after short-term follow-up was 0.79 (95% CI, 0.20-3.19); after intermediate follow-up the odds ratio was 0.72 (95% CI, 0.21-2.44).

This study, which included a symptom score after 3 months, favored treatment, with a weighted mean difference of -4.5, but with wide 95% CI of -10.28 to 1.28. An effect was demonstrated on clearing effusions in the short term, but the advantage appeared to vanish for the most part by 3 months. The study did not evaluate improvements in hearing.⁴

No adverse effects of intranasal steroid treatment were seen except for transient drops in cortisol levels in the Shapiro study, which tested dexamethasone. Approximately 8 randomized controlled trials using oral steroids with and without antibiotics for OME and chronic OME mirror a trend for short-term benefit of treatment, spontaneous resolution, and frequent recurrence.

In summary, limited evidence exists for short-term improvement of OME with intranasal steroids plus antibiotics, and no evidence exists for lasting beneficial effect on effusion or OME associated hearing loss.

TABLE
Clinical trials: Intranasal steroids for otitis media with effusion

Recommendations from others

The Canadian Task Force on Preventative Health Care found insufficient evidence to recommend screening for OME to prevent delayed language development.⁵

The Cochrane Ear, Nose and Throat Disorders Group concludes that both oral and topical intranasal steroids alone or in combination with an antibiotic lead to a quicker resolution of OME in the short term, but no long-term benefit is seen from treating OME effusions or associated hearing loss with topical intranasal steroids.⁶ They separately reviewed antibiotic treatment for OME, noting the short-term benefit above, but cited several drawbacks including cost and increased antibacterial resistance.⁷

The American Academy of Family Physicians Clinical Recommendation on Otitis Media with Effusion in Young Children does not recommend steroid medications for treatment of OME in a child of any age.⁸

ACKNOWLEDGMENTS

Thanks to Marianne Broers, MD for her translation of reference 1 from Dutch.

Evidence summary

Multiple methodological flaws have characterized studies trying to answer this question over the past 30 to 35 years. The companies manufacturing glucosamine have funded most studies. The overwhelming proportion of positive but marginal results raises the possibility of a publication bias (the tendency to publish only positive or supportive results), and the funding sources for the positive studies make that bias plausible.

Identified flaws in the studies include small sample size, inconsistent diagnostic criteria, variable disease sites, differing routes of administration, inconsistent doses, compositions and forms of glucosamine, the brief durations of studies, and poorly defined endpoints.¹ Those problems account for the relatively low quality scores of the studies used in meta-analyses, particularly in earlier ones. Quality scores range from 12% to 52% of optimal and make any definitive conclusions suspect.²

The magnitude of the treatment effect is variable. Meta-analyses demonstrate aggregate treatment effects ranging from 0.36 to 1.02— where a small effect is 0.2, a moderate effect is 0.5, and a large effect is 0.8.²

When more recent, higher-quality studies are analyzed, trends toward benefit and the effect sizes for glucosamine diminish but remain at aggregate values ranging from 0.26 to 0.44.^2-4 Statistically significant differences exist in some subgroup analyses and secondary endpoints.⁵  Typical trends suggest that glucosamine is superior to placebo for pain relief, and less effective but safer than nonsteroidal anti-inflammatory agents.⁶

Statements about safety are speculative given the brief duration of available trials, most of which lasted <10 weeks.⁶ Reported adverse effects are few. Mild gastrointestinal, skin, and constitutional symptoms predominate, but seldom at rates much higher than placebo.^3-4 Pain relief may require as much as 4 to 6 weeks of therapy, and short studies may not demonstrate these benefits. The possibility of site-specific benefits or a difference in effect from a different dose or form is impossible to determine based on the current literature.

Recommendations from others

The American College of Rheumatology Subcommittee on Osteoarthritis believes that it is too early to issue recommendations for use of glucosamine sulfate or chondroitin sulfate for treatment of osteoarthritis.⁷

The National Institutes of Health Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) began recruiting in May 2002. The design of this study is specifically directed at addressing the flaws of previous studies. This study will enroll 1588 patients at 13 study sites, and will use standardized products and doses with a single route of administration in a double-blinded, placebo-controlled fashion.

The GAIT study will measure change in joint space width (baseline to 2 years) and consists of 4 arms: glucosamine vs placebo, chondroitin vs placebo, glucosamine and chondroitin vs placebo, and celecoxib vs placebo. It is likely that the National Institute of Arthritis, Musculoskeletal and Skin Diseases, in collaboration with the National Center for Complementary and Alternative Medicine, will issue recommendations regarding the efficacy of glucosamine when the study is complete in 2005 or 2006. Updates are available at http://nccam.nih.gov/clinicaltrials/ glucosamine.htm.

Evidence summary

Multiple methodological flaws have characterized studies trying to answer this question over the past 30 to 35 years. The companies manufacturing glucosamine have funded most studies. The overwhelming proportion of positive but marginal results raises the possibility of a publication bias (the tendency to publish only positive or supportive results), and the funding sources for the positive studies make that bias plausible.

Identified flaws in the studies include small sample size, inconsistent diagnostic criteria, variable disease sites, differing routes of administration, inconsistent doses, compositions and forms of glucosamine, the brief durations of studies, and poorly defined endpoints.¹ Those problems account for the relatively low quality scores of the studies used in meta-analyses, particularly in earlier ones. Quality scores range from 12% to 52% of optimal and make any definitive conclusions suspect.²

The magnitude of the treatment effect is variable. Meta-analyses demonstrate aggregate treatment effects ranging from 0.36 to 1.02— where a small effect is 0.2, a moderate effect is 0.5, and a large effect is 0.8.²

When more recent, higher-quality studies are analyzed, trends toward benefit and the effect sizes for glucosamine diminish but remain at aggregate values ranging from 0.26 to 0.44.^2-4 Statistically significant differences exist in some subgroup analyses and secondary endpoints.⁵  Typical trends suggest that glucosamine is superior to placebo for pain relief, and less effective but safer than nonsteroidal anti-inflammatory agents.⁶

Statements about safety are speculative given the brief duration of available trials, most of which lasted <10 weeks.⁶ Reported adverse effects are few. Mild gastrointestinal, skin, and constitutional symptoms predominate, but seldom at rates much higher than placebo.^3-4 Pain relief may require as much as 4 to 6 weeks of therapy, and short studies may not demonstrate these benefits. The possibility of site-specific benefits or a difference in effect from a different dose or form is impossible to determine based on the current literature.

Recommendations from others

The American College of Rheumatology Subcommittee on Osteoarthritis believes that it is too early to issue recommendations for use of glucosamine sulfate or chondroitin sulfate for treatment of osteoarthritis.⁷

The National Institutes of Health Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) began recruiting in May 2002. The design of this study is specifically directed at addressing the flaws of previous studies. This study will enroll 1588 patients at 13 study sites, and will use standardized products and doses with a single route of administration in a double-blinded, placebo-controlled fashion.

The GAIT study will measure change in joint space width (baseline to 2 years) and consists of 4 arms: glucosamine vs placebo, chondroitin vs placebo, glucosamine and chondroitin vs placebo, and celecoxib vs placebo. It is likely that the National Institute of Arthritis, Musculoskeletal and Skin Diseases, in collaboration with the National Center for Complementary and Alternative Medicine, will issue recommendations regarding the efficacy of glucosamine when the study is complete in 2005 or 2006. Updates are available at http://nccam.nih.gov/clinicaltrials/ glucosamine.htm.

Evidence summary

Multiple methodological flaws have characterized studies trying to answer this question over the past 30 to 35 years. The companies manufacturing glucosamine have funded most studies. The overwhelming proportion of positive but marginal results raises the possibility of a publication bias (the tendency to publish only positive or supportive results), and the funding sources for the positive studies make that bias plausible.

Identified flaws in the studies include small sample size, inconsistent diagnostic criteria, variable disease sites, differing routes of administration, inconsistent doses, compositions and forms of glucosamine, the brief durations of studies, and poorly defined endpoints.¹ Those problems account for the relatively low quality scores of the studies used in meta-analyses, particularly in earlier ones. Quality scores range from 12% to 52% of optimal and make any definitive conclusions suspect.²

The magnitude of the treatment effect is variable. Meta-analyses demonstrate aggregate treatment effects ranging from 0.36 to 1.02— where a small effect is 0.2, a moderate effect is 0.5, and a large effect is 0.8.²

When more recent, higher-quality studies are analyzed, trends toward benefit and the effect sizes for glucosamine diminish but remain at aggregate values ranging from 0.26 to 0.44.^2-4 Statistically significant differences exist in some subgroup analyses and secondary endpoints.⁵  Typical trends suggest that glucosamine is superior to placebo for pain relief, and less effective but safer than nonsteroidal anti-inflammatory agents.⁶

Statements about safety are speculative given the brief duration of available trials, most of which lasted <10 weeks.⁶ Reported adverse effects are few. Mild gastrointestinal, skin, and constitutional symptoms predominate, but seldom at rates much higher than placebo.^3-4 Pain relief may require as much as 4 to 6 weeks of therapy, and short studies may not demonstrate these benefits. The possibility of site-specific benefits or a difference in effect from a different dose or form is impossible to determine based on the current literature.

Recommendations from others

The American College of Rheumatology Subcommittee on Osteoarthritis believes that it is too early to issue recommendations for use of glucosamine sulfate or chondroitin sulfate for treatment of osteoarthritis.⁷

The National Institutes of Health Glucosamine/Chondroitin Arthritis Intervention Trial (GAIT) began recruiting in May 2002. The design of this study is specifically directed at addressing the flaws of previous studies. This study will enroll 1588 patients at 13 study sites, and will use standardized products and doses with a single route of administration in a double-blinded, placebo-controlled fashion.

The GAIT study will measure change in joint space width (baseline to 2 years) and consists of 4 arms: glucosamine vs placebo, chondroitin vs placebo, glucosamine and chondroitin vs placebo, and celecoxib vs placebo. It is likely that the National Institute of Arthritis, Musculoskeletal and Skin Diseases, in collaboration with the National Center for Complementary and Alternative Medicine, will issue recommendations regarding the efficacy of glucosamine when the study is complete in 2005 or 2006. Updates are available at http://nccam.nih.gov/clinicaltrials/ glucosamine.htm.

Evidence summary

A well-done, prospective cohort study enrolled 229 patients (mean age, 66; 70% male) diagnosed with severe mitral regurgitation. Overall 10-year mortality was 43%. Older patients, those with New York Heart Association (NYHA) class III or IV heart failure, or those with left ventricular ejection fraction <60% had higher mortality. Eighty-two percent of patients had surgery within 10 years. Mortality among patients undergoing surgery was equivalent to that of the age-matched US population and significantly less than patients managed without surgery.¹

A second report from the same cohort compared the outcomes of patients undergoing early surgery (within 1 month of diagnosis) with those initially treated medically. Eight patients were excluded from this study because they were unsuitable candidates for surgery. The remaining 221 patients were followed based on their original group assignment of early surgery (63 patients) or medical management (158 patients).

Patients undergoing early surgery were more likely to have symptoms at enrollment than those managed medically. Patients in the early surgery group had better 5-year (89% vs 78%) and 10-year (78% vs 65%; P<.05 for both comparisons) survival and were less likely to develop congestive heart failure or atrial fibrillation. These differences remained significant after multivariate adjustment for potential confounders.²

Another cohort study of patients undergoing surgery for severe mitral regurgitation compared the outcomes of 199 patients with NYHA class I/II symptoms with those of 279 patients with NYHA class III/IV symptoms. Patients with NYHA class I/II had better operative outcomes (0.5% vs 5.4%) and better 5-year (90% vs 73%) and 10-year (76% vs 48%) survival than patients with more severe symptoms. In multivariate analysis, NYHA functional class remained inversely associated with survival.³

In a prospective study testing the ability of physical examination to identify severe mitral regurgitation, 170 consecutive patients with mitral regurgitation assessed by echocardiography underwent a clinical examination by internists or cardiologists blinded to the echocardiogram findings. The negative predictive value for absence of severe mitral regurgitation with a murmur less than grade III ranged from 88% to 100%. Murmurs greater than grade III had a predictive value of 91% for severe mitral regurgitation. Grade III murmurs were not predictive of severity.⁴

This study found no difference in the performance of internists and cardiologists. A systematic review found that cardiologists were able to accurately determine the presence or absence of mitral regurgitation by physical exam, but that trainees (internal medicine house staff and students) were much less accurate in their assessment.⁵

Recommendations from others

The American College of Cardiology and the American Heart Association recommend that patients with murmurs consistent with mitral regurgitation (holosytolic or late systolic murmurs) undergo echocardiography. Severity of regurgitation determined echocardiographically should dictate subsequent follow-up.

Patients with mild mitral regurgitation should undergo annual physical examination. Patients with moderate mitral regurgitation should undergo annual clinical evaluation and echocardiographic examination. Asymptomatic patients with severe mitral regurgitation should have a clinical and echocardiographic evaluation every 6 to 12 months. Patients with symptoms of heart failure or with mild left ventricular dysfunction (ejection fraction 50%-60% or end-diastolic dimension 45-50 mm) should be referred for surgery. Surgery should be considered in patients with severe mitral regurgitation and atrial fibrillation (SOR=D).⁶

Evidence summary

A well-done, prospective cohort study enrolled 229 patients (mean age, 66; 70% male) diagnosed with severe mitral regurgitation. Overall 10-year mortality was 43%. Older patients, those with New York Heart Association (NYHA) class III or IV heart failure, or those with left ventricular ejection fraction <60% had higher mortality. Eighty-two percent of patients had surgery within 10 years. Mortality among patients undergoing surgery was equivalent to that of the age-matched US population and significantly less than patients managed without surgery.¹

A second report from the same cohort compared the outcomes of patients undergoing early surgery (within 1 month of diagnosis) with those initially treated medically. Eight patients were excluded from this study because they were unsuitable candidates for surgery. The remaining 221 patients were followed based on their original group assignment of early surgery (63 patients) or medical management (158 patients).

Patients undergoing early surgery were more likely to have symptoms at enrollment than those managed medically. Patients in the early surgery group had better 5-year (89% vs 78%) and 10-year (78% vs 65%; P<.05 for both comparisons) survival and were less likely to develop congestive heart failure or atrial fibrillation. These differences remained significant after multivariate adjustment for potential confounders.²

Another cohort study of patients undergoing surgery for severe mitral regurgitation compared the outcomes of 199 patients with NYHA class I/II symptoms with those of 279 patients with NYHA class III/IV symptoms. Patients with NYHA class I/II had better operative outcomes (0.5% vs 5.4%) and better 5-year (90% vs 73%) and 10-year (76% vs 48%) survival than patients with more severe symptoms. In multivariate analysis, NYHA functional class remained inversely associated with survival.³

In a prospective study testing the ability of physical examination to identify severe mitral regurgitation, 170 consecutive patients with mitral regurgitation assessed by echocardiography underwent a clinical examination by internists or cardiologists blinded to the echocardiogram findings. The negative predictive value for absence of severe mitral regurgitation with a murmur less than grade III ranged from 88% to 100%. Murmurs greater than grade III had a predictive value of 91% for severe mitral regurgitation. Grade III murmurs were not predictive of severity.⁴

This study found no difference in the performance of internists and cardiologists. A systematic review found that cardiologists were able to accurately determine the presence or absence of mitral regurgitation by physical exam, but that trainees (internal medicine house staff and students) were much less accurate in their assessment.⁵

Recommendations from others

The American College of Cardiology and the American Heart Association recommend that patients with murmurs consistent with mitral regurgitation (holosytolic or late systolic murmurs) undergo echocardiography. Severity of regurgitation determined echocardiographically should dictate subsequent follow-up.

Patients with mild mitral regurgitation should undergo annual physical examination. Patients with moderate mitral regurgitation should undergo annual clinical evaluation and echocardiographic examination. Asymptomatic patients with severe mitral regurgitation should have a clinical and echocardiographic evaluation every 6 to 12 months. Patients with symptoms of heart failure or with mild left ventricular dysfunction (ejection fraction 50%-60% or end-diastolic dimension 45-50 mm) should be referred for surgery. Surgery should be considered in patients with severe mitral regurgitation and atrial fibrillation (SOR=D).⁶

Evidence summary

A well-done, prospective cohort study enrolled 229 patients (mean age, 66; 70% male) diagnosed with severe mitral regurgitation. Overall 10-year mortality was 43%. Older patients, those with New York Heart Association (NYHA) class III or IV heart failure, or those with left ventricular ejection fraction <60% had higher mortality. Eighty-two percent of patients had surgery within 10 years. Mortality among patients undergoing surgery was equivalent to that of the age-matched US population and significantly less than patients managed without surgery.¹

A second report from the same cohort compared the outcomes of patients undergoing early surgery (within 1 month of diagnosis) with those initially treated medically. Eight patients were excluded from this study because they were unsuitable candidates for surgery. The remaining 221 patients were followed based on their original group assignment of early surgery (63 patients) or medical management (158 patients).

Patients undergoing early surgery were more likely to have symptoms at enrollment than those managed medically. Patients in the early surgery group had better 5-year (89% vs 78%) and 10-year (78% vs 65%; P<.05 for both comparisons) survival and were less likely to develop congestive heart failure or atrial fibrillation. These differences remained significant after multivariate adjustment for potential confounders.²

Another cohort study of patients undergoing surgery for severe mitral regurgitation compared the outcomes of 199 patients with NYHA class I/II symptoms with those of 279 patients with NYHA class III/IV symptoms. Patients with NYHA class I/II had better operative outcomes (0.5% vs 5.4%) and better 5-year (90% vs 73%) and 10-year (76% vs 48%) survival than patients with more severe symptoms. In multivariate analysis, NYHA functional class remained inversely associated with survival.³

In a prospective study testing the ability of physical examination to identify severe mitral regurgitation, 170 consecutive patients with mitral regurgitation assessed by echocardiography underwent a clinical examination by internists or cardiologists blinded to the echocardiogram findings. The negative predictive value for absence of severe mitral regurgitation with a murmur less than grade III ranged from 88% to 100%. Murmurs greater than grade III had a predictive value of 91% for severe mitral regurgitation. Grade III murmurs were not predictive of severity.⁴

This study found no difference in the performance of internists and cardiologists. A systematic review found that cardiologists were able to accurately determine the presence or absence of mitral regurgitation by physical exam, but that trainees (internal medicine house staff and students) were much less accurate in their assessment.⁵

Recommendations from others

The American College of Cardiology and the American Heart Association recommend that patients with murmurs consistent with mitral regurgitation (holosytolic or late systolic murmurs) undergo echocardiography. Severity of regurgitation determined echocardiographically should dictate subsequent follow-up.

Patients with mild mitral regurgitation should undergo annual physical examination. Patients with moderate mitral regurgitation should undergo annual clinical evaluation and echocardiographic examination. Asymptomatic patients with severe mitral regurgitation should have a clinical and echocardiographic evaluation every 6 to 12 months. Patients with symptoms of heart failure or with mild left ventricular dysfunction (ejection fraction 50%-60% or end-diastolic dimension 45-50 mm) should be referred for surgery. Surgery should be considered in patients with severe mitral regurgitation and atrial fibrillation (SOR=D).⁶

Evidence summary

Studies of ankle sprain use variable diagnostic criteria for sprain and definition of recovery (return to play). They often report indirect outcomes such as edema. The effect of decreased edema on recovery time is not addressed.

Only 1 study has directly compared heat vs ice therapy and recovery time for ankle sprains. A retrospective cohort study of 32 patients in a sports medicine clinic demonstrated that early cryotherapy (within 36 hours of injury) for grades 3 and 4 ankle sprains, when compared with early heat therapy, resulted in earlier return to activity, as defined by ability to walk, climb stairs, run, and jump without pain.¹ Grade 3 sprains treated with ice recovered in 11.0 days vs 14.8 days with heat. Grade 4 sprains treated with ice recovered in 13.2 days vs 30.4 days with heat. This study also showed that early application of ice (within 36 hours) decreased time to recovery compared with late application of ice.

However, evidence is heterogeneous about the effect of ice on return to play. In 2 of 3 randomized controlled trials, early application of ice vs placebo did not significantly speed return to play.

One randomized controlled trial compared ice therapy (in the form of a cooling anklet applied upon presentation) with placebo in 143 patients presenting within 24 hours of injury to a university emergency department in England.² All patients received high-dose nonsteroidal anti-inflammatory agents. Though a trend was found in favor of ice therapy, no statistically significant difference was found in recovery time, as defined by pain relief and ability to bear weight. The grade of sprain was not specifically accounted for in this study.

Another randomized controlled trial compared ice with placebo in 30 patients with grade 3 and 4 sprains referred to a physiotherapy department within 2 days of ankle injury. No statistical difference was found in recovery time, defined as ability to bear weight with only mild to moderate pain.³

However, a randomized controlled trial of 60 patients with acute ankle sprains of all grades presenting to an emergency department compared cryogel plus bandaging with bandaging alone (cooling vs no cooling). This study found the mean time to recovery—defined as decreased pain—was reduced from 14.8 days to 9.7 days with constant cooling for the first 48 hours.⁴

The application of ice—but not heat—within 24 to 48 hours of acute ankle sprain also reduced edema. Several studies looked at reduction of edema with cooling. One study measured edema in 30 patients with grade 1 and 2 sprains treated with cold, heat, or contrast baths during the third, fourth, and fifth days.⁵ Only ice therapy alone significantly reduced edema.

Recommendations from others

The American Academy of Orthopaedic Surgeons recommends initial treatment of stable ankle sprains with rest, ice, gentle compression, and elevation (RICE).⁶ These guidelines are echoed by the American Academy of Family Physicians. In addition, the Institute for Clinical Systems Improvement and the National Guidelines Clearinghouse recommend PRICE, where protecting the ankle is explicitly added to RICE therapy.⁷

Evidence summary

Studies of ankle sprain use variable diagnostic criteria for sprain and definition of recovery (return to play). They often report indirect outcomes such as edema. The effect of decreased edema on recovery time is not addressed.

Only 1 study has directly compared heat vs ice therapy and recovery time for ankle sprains. A retrospective cohort study of 32 patients in a sports medicine clinic demonstrated that early cryotherapy (within 36 hours of injury) for grades 3 and 4 ankle sprains, when compared with early heat therapy, resulted in earlier return to activity, as defined by ability to walk, climb stairs, run, and jump without pain.¹ Grade 3 sprains treated with ice recovered in 11.0 days vs 14.8 days with heat. Grade 4 sprains treated with ice recovered in 13.2 days vs 30.4 days with heat. This study also showed that early application of ice (within 36 hours) decreased time to recovery compared with late application of ice.

However, evidence is heterogeneous about the effect of ice on return to play. In 2 of 3 randomized controlled trials, early application of ice vs placebo did not significantly speed return to play.

One randomized controlled trial compared ice therapy (in the form of a cooling anklet applied upon presentation) with placebo in 143 patients presenting within 24 hours of injury to a university emergency department in England.² All patients received high-dose nonsteroidal anti-inflammatory agents. Though a trend was found in favor of ice therapy, no statistically significant difference was found in recovery time, as defined by pain relief and ability to bear weight. The grade of sprain was not specifically accounted for in this study.

Another randomized controlled trial compared ice with placebo in 30 patients with grade 3 and 4 sprains referred to a physiotherapy department within 2 days of ankle injury. No statistical difference was found in recovery time, defined as ability to bear weight with only mild to moderate pain.³

However, a randomized controlled trial of 60 patients with acute ankle sprains of all grades presenting to an emergency department compared cryogel plus bandaging with bandaging alone (cooling vs no cooling). This study found the mean time to recovery—defined as decreased pain—was reduced from 14.8 days to 9.7 days with constant cooling for the first 48 hours.⁴

The application of ice—but not heat—within 24 to 48 hours of acute ankle sprain also reduced edema. Several studies looked at reduction of edema with cooling. One study measured edema in 30 patients with grade 1 and 2 sprains treated with cold, heat, or contrast baths during the third, fourth, and fifth days.⁵ Only ice therapy alone significantly reduced edema.

Recommendations from others

The American Academy of Orthopaedic Surgeons recommends initial treatment of stable ankle sprains with rest, ice, gentle compression, and elevation (RICE).⁶ These guidelines are echoed by the American Academy of Family Physicians. In addition, the Institute for Clinical Systems Improvement and the National Guidelines Clearinghouse recommend PRICE, where protecting the ankle is explicitly added to RICE therapy.⁷

Evidence summary

Studies of ankle sprain use variable diagnostic criteria for sprain and definition of recovery (return to play). They often report indirect outcomes such as edema. The effect of decreased edema on recovery time is not addressed.

Only 1 study has directly compared heat vs ice therapy and recovery time for ankle sprains. A retrospective cohort study of 32 patients in a sports medicine clinic demonstrated that early cryotherapy (within 36 hours of injury) for grades 3 and 4 ankle sprains, when compared with early heat therapy, resulted in earlier return to activity, as defined by ability to walk, climb stairs, run, and jump without pain.¹ Grade 3 sprains treated with ice recovered in 11.0 days vs 14.8 days with heat. Grade 4 sprains treated with ice recovered in 13.2 days vs 30.4 days with heat. This study also showed that early application of ice (within 36 hours) decreased time to recovery compared with late application of ice.

However, evidence is heterogeneous about the effect of ice on return to play. In 2 of 3 randomized controlled trials, early application of ice vs placebo did not significantly speed return to play.

One randomized controlled trial compared ice therapy (in the form of a cooling anklet applied upon presentation) with placebo in 143 patients presenting within 24 hours of injury to a university emergency department in England.² All patients received high-dose nonsteroidal anti-inflammatory agents. Though a trend was found in favor of ice therapy, no statistically significant difference was found in recovery time, as defined by pain relief and ability to bear weight. The grade of sprain was not specifically accounted for in this study.

Another randomized controlled trial compared ice with placebo in 30 patients with grade 3 and 4 sprains referred to a physiotherapy department within 2 days of ankle injury. No statistical difference was found in recovery time, defined as ability to bear weight with only mild to moderate pain.³

However, a randomized controlled trial of 60 patients with acute ankle sprains of all grades presenting to an emergency department compared cryogel plus bandaging with bandaging alone (cooling vs no cooling). This study found the mean time to recovery—defined as decreased pain—was reduced from 14.8 days to 9.7 days with constant cooling for the first 48 hours.⁴

The application of ice—but not heat—within 24 to 48 hours of acute ankle sprain also reduced edema. Several studies looked at reduction of edema with cooling. One study measured edema in 30 patients with grade 1 and 2 sprains treated with cold, heat, or contrast baths during the third, fourth, and fifth days.⁵ Only ice therapy alone significantly reduced edema.

Recommendations from others

The American Academy of Orthopaedic Surgeons recommends initial treatment of stable ankle sprains with rest, ice, gentle compression, and elevation (RICE).⁶ These guidelines are echoed by the American Academy of Family Physicians. In addition, the Institute for Clinical Systems Improvement and the National Guidelines Clearinghouse recommend PRICE, where protecting the ankle is explicitly added to RICE therapy.⁷