Gary Kelsberg, MD

EVIDENCE SUMMARY

A meta-analysis of 13 randomized, placebo or standard of care-controlled statin trials (113,148 patients, 81% without diabetes at enrollment, mean ages 55-76 years) found that statin therapy increased the incidence of diabetes by 9% over 4 years (odds ratio [OR]=1.09; 95% confidence interval [CI], 1.02-1.17), or one additional case per 255 patients.¹ The increased risk was similar for lipophilic (pravastatin, rosuvastatin) and hydrophilic (atorvastatin, simvastatin, lovastatin) statins, although the analysis wasn’t adjusted for doses used.

In a meta-regression analysis, baseline body mass index or percentage change in low-density lipoprotein cholesterol didn’t appear to confer additional risk. The risk of diabetes with statins was generally higher in studies with older patients (data given graphically).

Higher statin doses mean higher risk

A meta-analysis of 5 placebo and standard-of-care randomized controlled trials (39,612 patients, 83% without diabetes at enrollment, mean age 58-64 years) found that the risk of diabetes was higher with higher-dose statins.² Therapy with atorvastatin 80 mg or simvastatin 40 to 80 mg was defined as intensive. Treatment with simvastatin 20 to 40 mg, atorvastatin 10 mg, or pravastatin 40 mg was defined as moderate.

At a mean follow-up of 4.9 years, intensive statin therapy was associated with a higher risk of developing diabetes than moderate therapy (OR=1.12; 95% CI, 1.04-1.22) with 2 additional cases of diabetes per 1000 patient-years in the intensive therapy group. The authors noted significant heterogeneity between trials with regard to major cardiovascular events.

Similar results were found in a subsequent population-based cohort study of 471,250 nondiabetic patients older than 66 years who were newly prescribed a statin.³ The study authors used the incidence of new diabetes in patients taking pravastatin as the baseline, since it had been associated with reduced rates of diabetes in a large cardiovascular prevention trial.⁴ Without adjusting for dose, patients were at significantly higher risk of diabetes if prescribed atorvastatin (hazard ratio [HR]=1.22; 95% CI, 1.15-1.29), rosuvastatin (HR=1.18; 95% CI, 1.10-1.26), or simvastatin (HR=1.10; 95% CI, 1.04-1.17) compared with pravastatin. The risk with fluvastatin and lovastatin was similar to pravastatin.

A subanalysis that compared moderate- and high-dose statin therapy with low-dose therapy (atorvastatin <20 mg, rosuvastatin <10 mg, simvastatin <80 mg, or any dose of fluvastatin, lovastatin, or pravastatin) found a 22% increased risk of diabetes (HR=1.22; 95% CI, 1.19-1.26) for moderate-dose therapy (atorvastatin 20-79 mg, rosuvastatin 10-39 mg, or simvastatin >80 mg) and a 30% increased risk (HR=1.3; 95% CI, 1.2-1.4) for high-dose therapy (atorvastatin ≥80 mg or rosuvastatin ≥40 mg).

A cohort trial also shows increased diabetes risk

A smaller subsequent cohort trial based on data from Taiwan National Health Insurance records compared 8412 nondiabetic adult patients (mean age 63 years) taking statins with 33,648 age- and risk-matched controls not taking statins over a mean duration of 7.2 years.⁵ Statin use was associated with a 15% higher risk of developing diabetes (HR=1.15; 95% CI, 1.08-1.22).

RECOMMENDATIONS

The 2013 American College of Cardiology/American Heart Association guidelines for lipid-lowering therapy recommend that patients taking statins be screened for diabetes according to current screening recommendations.⁶ The guidelines advise encouraging patients who develop diabetes while on statin therapy to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of cardiovascular events.

EVIDENCE SUMMARY

A meta-analysis of 13 randomized, placebo or standard of care-controlled statin trials (113,148 patients, 81% without diabetes at enrollment, mean ages 55-76 years) found that statin therapy increased the incidence of diabetes by 9% over 4 years (odds ratio [OR]=1.09; 95% confidence interval [CI], 1.02-1.17), or one additional case per 255 patients.¹ The increased risk was similar for lipophilic (pravastatin, rosuvastatin) and hydrophilic (atorvastatin, simvastatin, lovastatin) statins, although the analysis wasn’t adjusted for doses used.

In a meta-regression analysis, baseline body mass index or percentage change in low-density lipoprotein cholesterol didn’t appear to confer additional risk. The risk of diabetes with statins was generally higher in studies with older patients (data given graphically).

Higher statin doses mean higher risk

A meta-analysis of 5 placebo and standard-of-care randomized controlled trials (39,612 patients, 83% without diabetes at enrollment, mean age 58-64 years) found that the risk of diabetes was higher with higher-dose statins.² Therapy with atorvastatin 80 mg or simvastatin 40 to 80 mg was defined as intensive. Treatment with simvastatin 20 to 40 mg, atorvastatin 10 mg, or pravastatin 40 mg was defined as moderate.

At a mean follow-up of 4.9 years, intensive statin therapy was associated with a higher risk of developing diabetes than moderate therapy (OR=1.12; 95% CI, 1.04-1.22) with 2 additional cases of diabetes per 1000 patient-years in the intensive therapy group. The authors noted significant heterogeneity between trials with regard to major cardiovascular events.

Similar results were found in a subsequent population-based cohort study of 471,250 nondiabetic patients older than 66 years who were newly prescribed a statin.³ The study authors used the incidence of new diabetes in patients taking pravastatin as the baseline, since it had been associated with reduced rates of diabetes in a large cardiovascular prevention trial.⁴ Without adjusting for dose, patients were at significantly higher risk of diabetes if prescribed atorvastatin (hazard ratio [HR]=1.22; 95% CI, 1.15-1.29), rosuvastatin (HR=1.18; 95% CI, 1.10-1.26), or simvastatin (HR=1.10; 95% CI, 1.04-1.17) compared with pravastatin. The risk with fluvastatin and lovastatin was similar to pravastatin.

A subanalysis that compared moderate- and high-dose statin therapy with low-dose therapy (atorvastatin <20 mg, rosuvastatin <10 mg, simvastatin <80 mg, or any dose of fluvastatin, lovastatin, or pravastatin) found a 22% increased risk of diabetes (HR=1.22; 95% CI, 1.19-1.26) for moderate-dose therapy (atorvastatin 20-79 mg, rosuvastatin 10-39 mg, or simvastatin >80 mg) and a 30% increased risk (HR=1.3; 95% CI, 1.2-1.4) for high-dose therapy (atorvastatin ≥80 mg or rosuvastatin ≥40 mg).

A cohort trial also shows increased diabetes risk

A smaller subsequent cohort trial based on data from Taiwan National Health Insurance records compared 8412 nondiabetic adult patients (mean age 63 years) taking statins with 33,648 age- and risk-matched controls not taking statins over a mean duration of 7.2 years.⁵ Statin use was associated with a 15% higher risk of developing diabetes (HR=1.15; 95% CI, 1.08-1.22).

RECOMMENDATIONS

The 2013 American College of Cardiology/American Heart Association guidelines for lipid-lowering therapy recommend that patients taking statins be screened for diabetes according to current screening recommendations.⁶ The guidelines advise encouraging patients who develop diabetes while on statin therapy to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of cardiovascular events.

EVIDENCE SUMMARY

A meta-analysis of 13 randomized, placebo or standard of care-controlled statin trials (113,148 patients, 81% without diabetes at enrollment, mean ages 55-76 years) found that statin therapy increased the incidence of diabetes by 9% over 4 years (odds ratio [OR]=1.09; 95% confidence interval [CI], 1.02-1.17), or one additional case per 255 patients.¹ The increased risk was similar for lipophilic (pravastatin, rosuvastatin) and hydrophilic (atorvastatin, simvastatin, lovastatin) statins, although the analysis wasn’t adjusted for doses used.

In a meta-regression analysis, baseline body mass index or percentage change in low-density lipoprotein cholesterol didn’t appear to confer additional risk. The risk of diabetes with statins was generally higher in studies with older patients (data given graphically).

Higher statin doses mean higher risk

A meta-analysis of 5 placebo and standard-of-care randomized controlled trials (39,612 patients, 83% without diabetes at enrollment, mean age 58-64 years) found that the risk of diabetes was higher with higher-dose statins.² Therapy with atorvastatin 80 mg or simvastatin 40 to 80 mg was defined as intensive. Treatment with simvastatin 20 to 40 mg, atorvastatin 10 mg, or pravastatin 40 mg was defined as moderate.

At a mean follow-up of 4.9 years, intensive statin therapy was associated with a higher risk of developing diabetes than moderate therapy (OR=1.12; 95% CI, 1.04-1.22) with 2 additional cases of diabetes per 1000 patient-years in the intensive therapy group. The authors noted significant heterogeneity between trials with regard to major cardiovascular events.

Similar results were found in a subsequent population-based cohort study of 471,250 nondiabetic patients older than 66 years who were newly prescribed a statin.³ The study authors used the incidence of new diabetes in patients taking pravastatin as the baseline, since it had been associated with reduced rates of diabetes in a large cardiovascular prevention trial.⁴ Without adjusting for dose, patients were at significantly higher risk of diabetes if prescribed atorvastatin (hazard ratio [HR]=1.22; 95% CI, 1.15-1.29), rosuvastatin (HR=1.18; 95% CI, 1.10-1.26), or simvastatin (HR=1.10; 95% CI, 1.04-1.17) compared with pravastatin. The risk with fluvastatin and lovastatin was similar to pravastatin.

A subanalysis that compared moderate- and high-dose statin therapy with low-dose therapy (atorvastatin <20 mg, rosuvastatin <10 mg, simvastatin <80 mg, or any dose of fluvastatin, lovastatin, or pravastatin) found a 22% increased risk of diabetes (HR=1.22; 95% CI, 1.19-1.26) for moderate-dose therapy (atorvastatin 20-79 mg, rosuvastatin 10-39 mg, or simvastatin >80 mg) and a 30% increased risk (HR=1.3; 95% CI, 1.2-1.4) for high-dose therapy (atorvastatin ≥80 mg or rosuvastatin ≥40 mg).

A cohort trial also shows increased diabetes risk

A smaller subsequent cohort trial based on data from Taiwan National Health Insurance records compared 8412 nondiabetic adult patients (mean age 63 years) taking statins with 33,648 age- and risk-matched controls not taking statins over a mean duration of 7.2 years.⁵ Statin use was associated with a 15% higher risk of developing diabetes (HR=1.15; 95% CI, 1.08-1.22).

RECOMMENDATIONS

The 2013 American College of Cardiology/American Heart Association guidelines for lipid-lowering therapy recommend that patients taking statins be screened for diabetes according to current screening recommendations.⁶ The guidelines advise encouraging patients who develop diabetes while on statin therapy to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce the risk of cardiovascular events.

EVIDENCE SUMMARY

A systematic review including 4 case-control and 3 cohort studies of the impact of nocturnal enuresis on children and young people found that bedwetting was often, but not always, associated with lower self-esteem scores (or scores for symptoms similar to lower self-esteem) on standardized questionnaires.¹ The studies defined self-esteem in various ways and used a variety of questionnaires to measure it, so direct comparisons weren’t possible.

The first case-control study in the review found that enuretic older children (10-12 years) and girls had lower self-esteem scores than younger children (8-9 years) and boys. The second case-control study reported lower self-esteem scores on only 1 of 3 assessment instruments.

The third case-control study, which compared self-esteem scores in enuretic children with scores for children who had asthma and heart disease, found that enuresis was associated with the lowest self-esteem. The final case-control study reported that young adolescents with enuresis were more likely to suffer “angry distress.”

The first cohort study in the systematic review found a significantly higher incidence of sadness, anxiety, and social fears in children with enuresis than in children without and reported that 65% were “not happy” about having enuresis.

In the second cohort study, children with more severe enuresis, and girls, had significantly worse self-esteem scores than children with mild enuresis or boys (actual scores and some statistics not supplied), although these findings weren’t replicated on the second standardized scale that the investigators used.

The third cohort study reported that 37% of approximately 800 children with enuresis rated it “really difficult,” on a 4-point Likert scale.

How enuresis treatment affects self-esteem

The same systematic review, plus 2 additional studies, demonstrated that successful treatment of enuresis improves self-esteem scores, likely to normal.^1-3 A randomized controlled trial found that treatment improved self-esteem scores by about 5%; children with the greatest treatment success showed the largest improvement (no statistics supplied).²

In a prospective cohort study, treated children demonstrated about a 30% improvement in scores measuring anxiety, depression, and internal distress.³ A case-control study in the systematic review also found about a 30% improvement in self-esteem scores among successfully treated children (both boys and girls) and a return to nonenuretic norms.¹ Scores for unsuccessfully treated children didn’t improve.

RECOMMENDATIONS

A guideline on the management of bedwetting from the National Institute for Health and Clinical Excellence (now called the National Institute for Health and Care Excellence) says that enuresis can have a deep impact on a child’s behavior and emotional well-being and that treatment has a positive effect on self-esteem.⁴

The Evidence-Based Medicine guidelines for enuresis in a child⁵ say that enuresis as such does not indicate a psychological disturbance and that psychotherapy may be useful when enuresis is associated with significant problems of self-esteem or behavior.

The American Academy of Child and Adolescent Psychiatry practice parameter for children with enuresis states that the psychological consequences of enuresis must be recognized and addressed with sensitivity during evaluation and management.⁶

EVIDENCE SUMMARY

A systematic review including 4 case-control and 3 cohort studies of the impact of nocturnal enuresis on children and young people found that bedwetting was often, but not always, associated with lower self-esteem scores (or scores for symptoms similar to lower self-esteem) on standardized questionnaires.¹ The studies defined self-esteem in various ways and used a variety of questionnaires to measure it, so direct comparisons weren’t possible.

The first case-control study in the review found that enuretic older children (10-12 years) and girls had lower self-esteem scores than younger children (8-9 years) and boys. The second case-control study reported lower self-esteem scores on only 1 of 3 assessment instruments.

The third case-control study, which compared self-esteem scores in enuretic children with scores for children who had asthma and heart disease, found that enuresis was associated with the lowest self-esteem. The final case-control study reported that young adolescents with enuresis were more likely to suffer “angry distress.”

The first cohort study in the systematic review found a significantly higher incidence of sadness, anxiety, and social fears in children with enuresis than in children without and reported that 65% were “not happy” about having enuresis.

In the second cohort study, children with more severe enuresis, and girls, had significantly worse self-esteem scores than children with mild enuresis or boys (actual scores and some statistics not supplied), although these findings weren’t replicated on the second standardized scale that the investigators used.

The third cohort study reported that 37% of approximately 800 children with enuresis rated it “really difficult,” on a 4-point Likert scale.

How enuresis treatment affects self-esteem

The same systematic review, plus 2 additional studies, demonstrated that successful treatment of enuresis improves self-esteem scores, likely to normal.^1-3 A randomized controlled trial found that treatment improved self-esteem scores by about 5%; children with the greatest treatment success showed the largest improvement (no statistics supplied).²

In a prospective cohort study, treated children demonstrated about a 30% improvement in scores measuring anxiety, depression, and internal distress.³ A case-control study in the systematic review also found about a 30% improvement in self-esteem scores among successfully treated children (both boys and girls) and a return to nonenuretic norms.¹ Scores for unsuccessfully treated children didn’t improve.

RECOMMENDATIONS

A guideline on the management of bedwetting from the National Institute for Health and Clinical Excellence (now called the National Institute for Health and Care Excellence) says that enuresis can have a deep impact on a child’s behavior and emotional well-being and that treatment has a positive effect on self-esteem.⁴

The Evidence-Based Medicine guidelines for enuresis in a child⁵ say that enuresis as such does not indicate a psychological disturbance and that psychotherapy may be useful when enuresis is associated with significant problems of self-esteem or behavior.

The American Academy of Child and Adolescent Psychiatry practice parameter for children with enuresis states that the psychological consequences of enuresis must be recognized and addressed with sensitivity during evaluation and management.⁶

EVIDENCE SUMMARY

A systematic review including 4 case-control and 3 cohort studies of the impact of nocturnal enuresis on children and young people found that bedwetting was often, but not always, associated with lower self-esteem scores (or scores for symptoms similar to lower self-esteem) on standardized questionnaires.¹ The studies defined self-esteem in various ways and used a variety of questionnaires to measure it, so direct comparisons weren’t possible.

The first case-control study in the review found that enuretic older children (10-12 years) and girls had lower self-esteem scores than younger children (8-9 years) and boys. The second case-control study reported lower self-esteem scores on only 1 of 3 assessment instruments.

The third case-control study, which compared self-esteem scores in enuretic children with scores for children who had asthma and heart disease, found that enuresis was associated with the lowest self-esteem. The final case-control study reported that young adolescents with enuresis were more likely to suffer “angry distress.”

The first cohort study in the systematic review found a significantly higher incidence of sadness, anxiety, and social fears in children with enuresis than in children without and reported that 65% were “not happy” about having enuresis.

In the second cohort study, children with more severe enuresis, and girls, had significantly worse self-esteem scores than children with mild enuresis or boys (actual scores and some statistics not supplied), although these findings weren’t replicated on the second standardized scale that the investigators used.

The third cohort study reported that 37% of approximately 800 children with enuresis rated it “really difficult,” on a 4-point Likert scale.

How enuresis treatment affects self-esteem

The same systematic review, plus 2 additional studies, demonstrated that successful treatment of enuresis improves self-esteem scores, likely to normal.^1-3 A randomized controlled trial found that treatment improved self-esteem scores by about 5%; children with the greatest treatment success showed the largest improvement (no statistics supplied).²

In a prospective cohort study, treated children demonstrated about a 30% improvement in scores measuring anxiety, depression, and internal distress.³ A case-control study in the systematic review also found about a 30% improvement in self-esteem scores among successfully treated children (both boys and girls) and a return to nonenuretic norms.¹ Scores for unsuccessfully treated children didn’t improve.

RECOMMENDATIONS

A guideline on the management of bedwetting from the National Institute for Health and Clinical Excellence (now called the National Institute for Health and Care Excellence) says that enuresis can have a deep impact on a child’s behavior and emotional well-being and that treatment has a positive effect on self-esteem.⁴

The Evidence-Based Medicine guidelines for enuresis in a child⁵ say that enuresis as such does not indicate a psychological disturbance and that psychotherapy may be useful when enuresis is associated with significant problems of self-esteem or behavior.

The American Academy of Child and Adolescent Psychiatry practice parameter for children with enuresis states that the psychological consequences of enuresis must be recognized and addressed with sensitivity during evaluation and management.⁶

EVIDENCE SUMMARY

Bupropion is the only Food and Drug Administration (FDA)-approved antidepressant recommended as a first-line pharmacologic agent to assist with smoking cessation, based in part on a meta-analysis of 44 placebo-controlled RCTs (13,728 patients), which found that bupropion had a relative risk (RR) of 1.62 for smoking cessation compared with placebo (95% confidence interval [CI], 1.49-1.76). Bupropion produced quit rates that were approximately double those of placebo rates (18% [range 4%-43%] for bupropion vs 9% [range 0%-18%] for placebo).¹

Nortriptyline is also effective, 
other antidepressants not so much


A Cochrane systematic review of 10 antidepressants used for smoking cessation included 64 placebo-controlled trials, measuring at least 6-month abstinence rates as primary outcomes, and monitoring biochemical markers (such as breath carbon monoxide and urinary cotinine) to verify abstinence. Some trials included participants with previous depressive episodes, but most didn’t enroll patients with active major depression.¹ The TABLE¹ gives an overview of the studies and outcomes.

Nortriptyline, which was evaluated in 6 trials, was the only antidepressant besides bupropion that was superior to placebo.¹ Two of the nortriptyline trials included participants with active depression and the other trials had participants with a history of depression.Combining nortriptyline and nicotine replacement therapy (NRT) doesn’t increase quit rates compared with NRT alone. One trial found no difference in quit rates for patients taking nortriptyline with or without a history of major depression, although the subgroups were small. Two trials measured quit rates for 12 months whereas the other 4 trials used 6-month quit rates.

Four additional RCTs with 1644 patients that combined nortriptyline with NRT found no improvement in quit rates compared with NRT alone (RR=1.21; 95% CI, 0.94-1.55).¹ Three RCTs with 417 patients compared bupropion with nortriptyline and found no difference (RR=1.3; 95% CI, 0.93-1.8).¹

SSRIs. None of the 4 SSRIs investigated in the trials (fluoxetine, paroxetine, sertraline, citalopram) improved smoking cessation rates more than placebo.¹ The 5 RCTs that studied the drugs followed participants for as long as a year. None of the participants were depressed at the time of the studies, although some had a history of depression.

The sertraline RCT used individual counseling sessions in conjunction with either sertraline or placebo. All participants had a history of major depression.

The paroxetine trial used NRT in all patients randomized to either paroxetine or placebo.

Venlafaxine. The serotonin-norepinephrine reuptake inhibitor venlafaxine didn’t improve smoking cessation rates over 12 months.¹

MAOIs. Neither of the 2 MAOIs increased smoking cessation rates.¹ The moclobemide RCT followed participants for 12 months; the 5 selegiline RCTs followed participants for as long as 6 months.

Other antidepressants. An RCT with 19 participants found that doxepin didn’t improve smoking cessation at 2 months.¹ One RCT and one open, randomized trial of St. John’s wort found no benefit for smoking cessation.^1,2

RECOMMENDATIONS

The United States Public Health Service (USPHS) and the University of Michigan Health System (UMHS) guidelines recommend the following FDA-approved pharmacotherapies as first-line agents for smoking cessation: sustained-release bupropion, NRT (gum, inhaler, lozenge, nasal spray, or patch), and varenicline.^3,4 They say that clonidine and nortriptyline are also effective but recommend them as second-line agents because these drugs lack FDA approval for this purpose.

The USPHS also recommends combinations of NRT and bupropion for long-term use. Because of additional cost and limited benefit, UMHS recommends reserving NRT-bupropion combination therapy for highly addicted tobacco users who have several failed quit attempts.

The United States Preventive Services Task Force guideline emphasizes counseling and interventions to prevent tobacco use; it doesn’t provide recommendations for pharmacotherapy.⁵ It does cite the same agents recommended by USPHS and UMHS as effective.

EVIDENCE SUMMARY

Bupropion is the only Food and Drug Administration (FDA)-approved antidepressant recommended as a first-line pharmacologic agent to assist with smoking cessation, based in part on a meta-analysis of 44 placebo-controlled RCTs (13,728 patients), which found that bupropion had a relative risk (RR) of 1.62 for smoking cessation compared with placebo (95% confidence interval [CI], 1.49-1.76). Bupropion produced quit rates that were approximately double those of placebo rates (18% [range 4%-43%] for bupropion vs 9% [range 0%-18%] for placebo).¹

Nortriptyline is also effective, 
other antidepressants not so much


A Cochrane systematic review of 10 antidepressants used for smoking cessation included 64 placebo-controlled trials, measuring at least 6-month abstinence rates as primary outcomes, and monitoring biochemical markers (such as breath carbon monoxide and urinary cotinine) to verify abstinence. Some trials included participants with previous depressive episodes, but most didn’t enroll patients with active major depression.¹ The TABLE¹ gives an overview of the studies and outcomes.

Nortriptyline, which was evaluated in 6 trials, was the only antidepressant besides bupropion that was superior to placebo.¹ Two of the nortriptyline trials included participants with active depression and the other trials had participants with a history of depression.Combining nortriptyline and nicotine replacement therapy (NRT) doesn’t increase quit rates compared with NRT alone. One trial found no difference in quit rates for patients taking nortriptyline with or without a history of major depression, although the subgroups were small. Two trials measured quit rates for 12 months whereas the other 4 trials used 6-month quit rates.

Four additional RCTs with 1644 patients that combined nortriptyline with NRT found no improvement in quit rates compared with NRT alone (RR=1.21; 95% CI, 0.94-1.55).¹ Three RCTs with 417 patients compared bupropion with nortriptyline and found no difference (RR=1.3; 95% CI, 0.93-1.8).¹

SSRIs. None of the 4 SSRIs investigated in the trials (fluoxetine, paroxetine, sertraline, citalopram) improved smoking cessation rates more than placebo.¹ The 5 RCTs that studied the drugs followed participants for as long as a year. None of the participants were depressed at the time of the studies, although some had a history of depression.

The sertraline RCT used individual counseling sessions in conjunction with either sertraline or placebo. All participants had a history of major depression.

The paroxetine trial used NRT in all patients randomized to either paroxetine or placebo.

Venlafaxine. The serotonin-norepinephrine reuptake inhibitor venlafaxine didn’t improve smoking cessation rates over 12 months.¹

MAOIs. Neither of the 2 MAOIs increased smoking cessation rates.¹ The moclobemide RCT followed participants for 12 months; the 5 selegiline RCTs followed participants for as long as 6 months.

Other antidepressants. An RCT with 19 participants found that doxepin didn’t improve smoking cessation at 2 months.¹ One RCT and one open, randomized trial of St. John’s wort found no benefit for smoking cessation.^1,2

RECOMMENDATIONS

The United States Public Health Service (USPHS) and the University of Michigan Health System (UMHS) guidelines recommend the following FDA-approved pharmacotherapies as first-line agents for smoking cessation: sustained-release bupropion, NRT (gum, inhaler, lozenge, nasal spray, or patch), and varenicline.^3,4 They say that clonidine and nortriptyline are also effective but recommend them as second-line agents because these drugs lack FDA approval for this purpose.

The USPHS also recommends combinations of NRT and bupropion for long-term use. Because of additional cost and limited benefit, UMHS recommends reserving NRT-bupropion combination therapy for highly addicted tobacco users who have several failed quit attempts.

The United States Preventive Services Task Force guideline emphasizes counseling and interventions to prevent tobacco use; it doesn’t provide recommendations for pharmacotherapy.⁵ It does cite the same agents recommended by USPHS and UMHS as effective.

EVIDENCE SUMMARY

Bupropion is the only Food and Drug Administration (FDA)-approved antidepressant recommended as a first-line pharmacologic agent to assist with smoking cessation, based in part on a meta-analysis of 44 placebo-controlled RCTs (13,728 patients), which found that bupropion had a relative risk (RR) of 1.62 for smoking cessation compared with placebo (95% confidence interval [CI], 1.49-1.76). Bupropion produced quit rates that were approximately double those of placebo rates (18% [range 4%-43%] for bupropion vs 9% [range 0%-18%] for placebo).¹

Nortriptyline is also effective, 
other antidepressants not so much


A Cochrane systematic review of 10 antidepressants used for smoking cessation included 64 placebo-controlled trials, measuring at least 6-month abstinence rates as primary outcomes, and monitoring biochemical markers (such as breath carbon monoxide and urinary cotinine) to verify abstinence. Some trials included participants with previous depressive episodes, but most didn’t enroll patients with active major depression.¹ The TABLE¹ gives an overview of the studies and outcomes.

Nortriptyline, which was evaluated in 6 trials, was the only antidepressant besides bupropion that was superior to placebo.¹ Two of the nortriptyline trials included participants with active depression and the other trials had participants with a history of depression.Combining nortriptyline and nicotine replacement therapy (NRT) doesn’t increase quit rates compared with NRT alone. One trial found no difference in quit rates for patients taking nortriptyline with or without a history of major depression, although the subgroups were small. Two trials measured quit rates for 12 months whereas the other 4 trials used 6-month quit rates.

Four additional RCTs with 1644 patients that combined nortriptyline with NRT found no improvement in quit rates compared with NRT alone (RR=1.21; 95% CI, 0.94-1.55).¹ Three RCTs with 417 patients compared bupropion with nortriptyline and found no difference (RR=1.3; 95% CI, 0.93-1.8).¹

SSRIs. None of the 4 SSRIs investigated in the trials (fluoxetine, paroxetine, sertraline, citalopram) improved smoking cessation rates more than placebo.¹ The 5 RCTs that studied the drugs followed participants for as long as a year. None of the participants were depressed at the time of the studies, although some had a history of depression.

The sertraline RCT used individual counseling sessions in conjunction with either sertraline or placebo. All participants had a history of major depression.

The paroxetine trial used NRT in all patients randomized to either paroxetine or placebo.

Venlafaxine. The serotonin-norepinephrine reuptake inhibitor venlafaxine didn’t improve smoking cessation rates over 12 months.¹

MAOIs. Neither of the 2 MAOIs increased smoking cessation rates.¹ The moclobemide RCT followed participants for 12 months; the 5 selegiline RCTs followed participants for as long as 6 months.

Other antidepressants. An RCT with 19 participants found that doxepin didn’t improve smoking cessation at 2 months.¹ One RCT and one open, randomized trial of St. John’s wort found no benefit for smoking cessation.^1,2

RECOMMENDATIONS

The United States Public Health Service (USPHS) and the University of Michigan Health System (UMHS) guidelines recommend the following FDA-approved pharmacotherapies as first-line agents for smoking cessation: sustained-release bupropion, NRT (gum, inhaler, lozenge, nasal spray, or patch), and varenicline.^3,4 They say that clonidine and nortriptyline are also effective but recommend them as second-line agents because these drugs lack FDA approval for this purpose.

The USPHS also recommends combinations of NRT and bupropion for long-term use. Because of additional cost and limited benefit, UMHS recommends reserving NRT-bupropion combination therapy for highly addicted tobacco users who have several failed quit attempts.

The United States Preventive Services Task Force guideline emphasizes counseling and interventions to prevent tobacco use; it doesn’t provide recommendations for pharmacotherapy.⁵ It does cite the same agents recommended by USPHS and UMHS as effective.

EVIDENCE SUMMARY

A systematic review of the effect of combined OCPs on women with a family history of breast cancer found no additional increase in risk.¹ Investigators identified 3 retrospective cohort studies (N=66,500, with 8500 cases) and 7 case-control studies (total 10,500 cases) from the past 40 years, most including women from the United States and Canada, but one including women from 5 continents.

In most trials, women of reproductive age using combined OCPs had 1 or more first-degree female relatives with breast cancer, although a few trials also included second-degree relatives. Women ranged in age from 20 to 79 years at diagnosis, and most trials controlled for age, parity, menstrual and menopausal history, duration of OCP exposure, and age at first use. Follow-up intervals for the retrospective cohort studies ranged from 5 to 16 years. Investigators were unable to combine results because of heterogenous populations.

Three of the cohort studies found no significant difference in breast cancer risk between OCP users and nonusers, regardless of age or duration of use. One cohort study found an increased risk in women taking older, higher-dose OCPs from before 1975 (relative risk [RR]=3.3; 95% confidence interval [CI], 1.5-7.2). All of the case-control studies found no significant difference in breast cancer risk for any age of starting, duration of OCP use, or degree of relative with breast cancer.

A meta-analysis of 54 case-control studies (6757 cases), comprising approximately 90% of the epidemiologic information on this topic, also found no significant difference in breast cancer risk related to OCP use among women with one or more first-degree relatives with breast cancer.² Investigators found that neither recent OCP use (<10 years, RR=0.77; 95% CI, 0.54-1.11) nor past OCP use (>10 years, RR=1.01; 95% CI, 0.80-1.28) affected risk of developing breast cancer.

Three additional case-control studies involving women with a family history of breast cancer also found no significant association for breast cancer incidence among OCP users compared with nonusers.^3-5

A meta-analysis of 5 studies (one retrospective cohort, 4 case-control, with a total of 2855 breast cancer cases and 2944 controls) evaluated whether combined OCPs increased the risk of breast cancer in women, all of whom were carrying BRCA1/2 mutations.⁶

Using modern combined OCPs didn’t raise the risk of breast cancer in BRCA1/2 carriers overall (RR=1.13; 95% CI, 0.88-1.45) or separately in BRCA1 carriers (5 studies, RR=1.09; 95% CI, 0.77-1.54) or BRCA2 carriers (3 studies, RR=1.15; 95% CI, 0.88-1.45).

However, pre-1975 (higher dose) combined OCPs produced significantly increased risk (RR=1.47; 95% CI, 1.06-2.04). Similarly, women who had used combined OCPs >10 years before the study (older women, likely to have been using pre-1975 OCPs) also had significantly increased risk (RR=1.46; 95% CI, 1.07-2.07).

A bit of good news:
 Combined OCPs reduce ovarian cancer risk

The analysis also determined that combined OCPs significantly reduced the risk of ovarian cancer in women carrying BRCA1/2 mutations (RR=0.50; 95% CI, 0.33-0.75), with an additional linear decrease in risk for each 10 years of OCP use (RR=0.64; 95% CI, 0.53-0.78).

RECOMMENDATIONS

Combined oral contraceptive pills significantly reduced the risk of ovarian cancer in women carrying BRCA1/2 mutations. The World Health Organization guidelines outlining criteria for contraceptive use state that OCPs don’t alter the risk of breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes.⁷

The American College of Obstetricians and Gynecologists (ACOG) says that a positive family history of breast cancer shouldn’t be regarded as a contraindication to OCP use.⁸ ACOG also says that women with the BRCA1 mutation have an increased risk of breast cancer if they used OCPs for longer than 5 years before age 30, but this risk may be more than balanced by the benefit of a greatly reduced risk of ovarian cancer.

EVIDENCE SUMMARY

A systematic review of the effect of combined OCPs on women with a family history of breast cancer found no additional increase in risk.¹ Investigators identified 3 retrospective cohort studies (N=66,500, with 8500 cases) and 7 case-control studies (total 10,500 cases) from the past 40 years, most including women from the United States and Canada, but one including women from 5 continents.

In most trials, women of reproductive age using combined OCPs had 1 or more first-degree female relatives with breast cancer, although a few trials also included second-degree relatives. Women ranged in age from 20 to 79 years at diagnosis, and most trials controlled for age, parity, menstrual and menopausal history, duration of OCP exposure, and age at first use. Follow-up intervals for the retrospective cohort studies ranged from 5 to 16 years. Investigators were unable to combine results because of heterogenous populations.

Three of the cohort studies found no significant difference in breast cancer risk between OCP users and nonusers, regardless of age or duration of use. One cohort study found an increased risk in women taking older, higher-dose OCPs from before 1975 (relative risk [RR]=3.3; 95% confidence interval [CI], 1.5-7.2). All of the case-control studies found no significant difference in breast cancer risk for any age of starting, duration of OCP use, or degree of relative with breast cancer.

A meta-analysis of 54 case-control studies (6757 cases), comprising approximately 90% of the epidemiologic information on this topic, also found no significant difference in breast cancer risk related to OCP use among women with one or more first-degree relatives with breast cancer.² Investigators found that neither recent OCP use (<10 years, RR=0.77; 95% CI, 0.54-1.11) nor past OCP use (>10 years, RR=1.01; 95% CI, 0.80-1.28) affected risk of developing breast cancer.

Three additional case-control studies involving women with a family history of breast cancer also found no significant association for breast cancer incidence among OCP users compared with nonusers.^3-5

A meta-analysis of 5 studies (one retrospective cohort, 4 case-control, with a total of 2855 breast cancer cases and 2944 controls) evaluated whether combined OCPs increased the risk of breast cancer in women, all of whom were carrying BRCA1/2 mutations.⁶

Using modern combined OCPs didn’t raise the risk of breast cancer in BRCA1/2 carriers overall (RR=1.13; 95% CI, 0.88-1.45) or separately in BRCA1 carriers (5 studies, RR=1.09; 95% CI, 0.77-1.54) or BRCA2 carriers (3 studies, RR=1.15; 95% CI, 0.88-1.45).

However, pre-1975 (higher dose) combined OCPs produced significantly increased risk (RR=1.47; 95% CI, 1.06-2.04). Similarly, women who had used combined OCPs >10 years before the study (older women, likely to have been using pre-1975 OCPs) also had significantly increased risk (RR=1.46; 95% CI, 1.07-2.07).

A bit of good news:
 Combined OCPs reduce ovarian cancer risk

The analysis also determined that combined OCPs significantly reduced the risk of ovarian cancer in women carrying BRCA1/2 mutations (RR=0.50; 95% CI, 0.33-0.75), with an additional linear decrease in risk for each 10 years of OCP use (RR=0.64; 95% CI, 0.53-0.78).

RECOMMENDATIONS

Combined oral contraceptive pills significantly reduced the risk of ovarian cancer in women carrying BRCA1/2 mutations. The World Health Organization guidelines outlining criteria for contraceptive use state that OCPs don’t alter the risk of breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes.⁷

The American College of Obstetricians and Gynecologists (ACOG) says that a positive family history of breast cancer shouldn’t be regarded as a contraindication to OCP use.⁸ ACOG also says that women with the BRCA1 mutation have an increased risk of breast cancer if they used OCPs for longer than 5 years before age 30, but this risk may be more than balanced by the benefit of a greatly reduced risk of ovarian cancer.

EVIDENCE SUMMARY

A systematic review of the effect of combined OCPs on women with a family history of breast cancer found no additional increase in risk.¹ Investigators identified 3 retrospective cohort studies (N=66,500, with 8500 cases) and 7 case-control studies (total 10,500 cases) from the past 40 years, most including women from the United States and Canada, but one including women from 5 continents.

In most trials, women of reproductive age using combined OCPs had 1 or more first-degree female relatives with breast cancer, although a few trials also included second-degree relatives. Women ranged in age from 20 to 79 years at diagnosis, and most trials controlled for age, parity, menstrual and menopausal history, duration of OCP exposure, and age at first use. Follow-up intervals for the retrospective cohort studies ranged from 5 to 16 years. Investigators were unable to combine results because of heterogenous populations.

Three of the cohort studies found no significant difference in breast cancer risk between OCP users and nonusers, regardless of age or duration of use. One cohort study found an increased risk in women taking older, higher-dose OCPs from before 1975 (relative risk [RR]=3.3; 95% confidence interval [CI], 1.5-7.2). All of the case-control studies found no significant difference in breast cancer risk for any age of starting, duration of OCP use, or degree of relative with breast cancer.

A meta-analysis of 54 case-control studies (6757 cases), comprising approximately 90% of the epidemiologic information on this topic, also found no significant difference in breast cancer risk related to OCP use among women with one or more first-degree relatives with breast cancer.² Investigators found that neither recent OCP use (<10 years, RR=0.77; 95% CI, 0.54-1.11) nor past OCP use (>10 years, RR=1.01; 95% CI, 0.80-1.28) affected risk of developing breast cancer.

Three additional case-control studies involving women with a family history of breast cancer also found no significant association for breast cancer incidence among OCP users compared with nonusers.^3-5

A meta-analysis of 5 studies (one retrospective cohort, 4 case-control, with a total of 2855 breast cancer cases and 2944 controls) evaluated whether combined OCPs increased the risk of breast cancer in women, all of whom were carrying BRCA1/2 mutations.⁶

Using modern combined OCPs didn’t raise the risk of breast cancer in BRCA1/2 carriers overall (RR=1.13; 95% CI, 0.88-1.45) or separately in BRCA1 carriers (5 studies, RR=1.09; 95% CI, 0.77-1.54) or BRCA2 carriers (3 studies, RR=1.15; 95% CI, 0.88-1.45).

However, pre-1975 (higher dose) combined OCPs produced significantly increased risk (RR=1.47; 95% CI, 1.06-2.04). Similarly, women who had used combined OCPs >10 years before the study (older women, likely to have been using pre-1975 OCPs) also had significantly increased risk (RR=1.46; 95% CI, 1.07-2.07).

A bit of good news:
 Combined OCPs reduce ovarian cancer risk

The analysis also determined that combined OCPs significantly reduced the risk of ovarian cancer in women carrying BRCA1/2 mutations (RR=0.50; 95% CI, 0.33-0.75), with an additional linear decrease in risk for each 10 years of OCP use (RR=0.64; 95% CI, 0.53-0.78).

RECOMMENDATIONS

Combined oral contraceptive pills significantly reduced the risk of ovarian cancer in women carrying BRCA1/2 mutations. The World Health Organization guidelines outlining criteria for contraceptive use state that OCPs don’t alter the risk of breast cancer among women with either a family history of breast cancer or breast cancer susceptibility genes.⁷

The American College of Obstetricians and Gynecologists (ACOG) says that a positive family history of breast cancer shouldn’t be regarded as a contraindication to OCP use.⁸ ACOG also says that women with the BRCA1 mutation have an increased risk of breast cancer if they used OCPs for longer than 5 years before age 30, but this risk may be more than balanced by the benefit of a greatly reduced risk of ovarian cancer.

EVIDENCE SUMMARY

A small RCT found that NTG therapy improved short-term pain and joint mobility in patients with acute supraspinatus tendinitis.¹ Investigators randomized 10 men and 10 women with acute shoulder tendonitis (fewer than 7 days’ duration) to use either 5-mg NTG patches or placebo patches daily for 3 days. Patients rated pain on a 10-point scale, and investigators measured joint mobility on a 4-point scale.

After 48 hours of treatment, NTG patches significantly reduced pain ratings from baseline (from 7 to 2 points; P<.001), whereas placebo didn’t (6 vs 6 points; P not significant). NTG patches also improved joint mobility from baseline (from 2 points “moderately restricted” to .1 points “not restricted”; P<.001), but placebo didn’t (1.2 points “mildly restricted” vs 1.2 points; P not significant). The placebo group had less pain and joint restriction than the NTG group at the start of the study. Two patients reported headache 24 hours after starting treatment.

A double-blind RCT evaluating NTG patches for 53 patients (57 shoulders) with chronic supraspinatus tendinopathy (shoulder pain lasting longer than 3 months) found that they improved pain, strength, and range of motion at 3 to 6 months.² Investigators randomized patients to receive one-quarter of a 5-mg 24-hour NTG patch or placebo patch daily and enrolled all patients in a rehabilitation program. They assessed subjective pain (at night and with activity), strength, and external rotation at baseline and at 2, 6, 12, and 24 weeks.

NTG patches improved nighttime pain about 30% (at 12 and 24 weeks), pain with activity about 60% (at 24 weeks), strength about 10% (at 12 and 24 weeks), and range of motion about 20% (at 24 weeks; P<.05 for all comparisons). The placebo group initially had more pain, less strength, and less mobility than the NTG group. Investigators reported no adverse effects.

NTG and rehab improve elbow pain, 
but with side effects


Another RCT comparing topical NTG patches in patients with chronic extensor tendinosis of the elbow found that they improved most parameters.³ Investigators randomized 86 patients with elbow tendonitis (longer than 3 months) to NTG patches (one-quarter of a 5-mg 24-hour patch) or placebo patches and enrolled all patients in a tendon rehabilitation program. They assessed subjective pain, extensor tendon tenderness, and muscle strength at baseline and at 2, 6, 12, and 24 weeks.

Topical nitroglycerin patches improve subjective pain scores by about 30% and range of motion over 3 days in patients with acute shoulder tendinopathy. NTG patches improved subjective pain, tendon tenderness, and strength significantly more than placebo at all follow-up points, by 15% to 50% (P<.05 for all comparisons). The study was flawed because the control group started with more pain, tenderness, and weakness than the NTG group. Five patients discontinued NTG because of adverse effects (headache, dermatitis, and facial flushing).

A follow-up study done 5 years after discontinuation of therapy found equal outcomes with NTG and placebo.⁴ Investigators evaluated, by phone or in person, 58 of the 86 patients in the original study. NTG and placebo therapy produced equivalent reductions in subjective 0 to 4 elbow pain scores over baseline (average pain 2.5 initially, 1.5 at 12 weeks, and 1.0 at 5 years; P<.01 for all comparisons with baseline, no significant difference between nitrates and placebo).

Another RCT that evaluated 3 different doses of NTG patches for 8 weeks in 154 patients with chronic lateral epicondylosis found NTG treatment was no better than placebo for pain or strength.⁵ Investigators randomized patients with more than 3 months of symptoms to 3 NTG patch doses (.72 mg/24 h, 1.44 mg/ 24 h, or 3.6 mg/24 h) compared with placebo and evaluated subjective pain (at rest, with activity, and at night), grip strength, and force, at baseline and 8 weeks.

The study lacked a formal wrist strengthening rehabilitation program. Patients in the placebo group had lower baseline pain scores than the NTG groups. Seven patients dropped out of the study because of headaches.

RECOMMENDATIONS

We found no authoritative recommendations regarding the use of topical nitrates for upper extremity tendinopathies.

An online reference text doesn’t make a recommendation, but references the studies described previously.⁶ The authors state that headache is the most common adverse effect of topical nitrates, but it becomes less severe over the course of treatment. They recommend caution in patients with hypotension, pregnancy, or migraines, and those who take diuretics. The authors also note that nitrates are relatively contraindicated in patients with ischemic heart disease, anemia, phosphodiesterase inhibitor therapy (such as sildenafil), angle-closure glaucoma, and allergy to nitrates.

EVIDENCE SUMMARY

A small RCT found that NTG therapy improved short-term pain and joint mobility in patients with acute supraspinatus tendinitis.¹ Investigators randomized 10 men and 10 women with acute shoulder tendonitis (fewer than 7 days’ duration) to use either 5-mg NTG patches or placebo patches daily for 3 days. Patients rated pain on a 10-point scale, and investigators measured joint mobility on a 4-point scale.

After 48 hours of treatment, NTG patches significantly reduced pain ratings from baseline (from 7 to 2 points; P<.001), whereas placebo didn’t (6 vs 6 points; P not significant). NTG patches also improved joint mobility from baseline (from 2 points “moderately restricted” to .1 points “not restricted”; P<.001), but placebo didn’t (1.2 points “mildly restricted” vs 1.2 points; P not significant). The placebo group had less pain and joint restriction than the NTG group at the start of the study. Two patients reported headache 24 hours after starting treatment.

A double-blind RCT evaluating NTG patches for 53 patients (57 shoulders) with chronic supraspinatus tendinopathy (shoulder pain lasting longer than 3 months) found that they improved pain, strength, and range of motion at 3 to 6 months.² Investigators randomized patients to receive one-quarter of a 5-mg 24-hour NTG patch or placebo patch daily and enrolled all patients in a rehabilitation program. They assessed subjective pain (at night and with activity), strength, and external rotation at baseline and at 2, 6, 12, and 24 weeks.

NTG patches improved nighttime pain about 30% (at 12 and 24 weeks), pain with activity about 60% (at 24 weeks), strength about 10% (at 12 and 24 weeks), and range of motion about 20% (at 24 weeks; P<.05 for all comparisons). The placebo group initially had more pain, less strength, and less mobility than the NTG group. Investigators reported no adverse effects.

NTG and rehab improve elbow pain, 
but with side effects


Another RCT comparing topical NTG patches in patients with chronic extensor tendinosis of the elbow found that they improved most parameters.³ Investigators randomized 86 patients with elbow tendonitis (longer than 3 months) to NTG patches (one-quarter of a 5-mg 24-hour patch) or placebo patches and enrolled all patients in a tendon rehabilitation program. They assessed subjective pain, extensor tendon tenderness, and muscle strength at baseline and at 2, 6, 12, and 24 weeks.

Topical nitroglycerin patches improve subjective pain scores by about 30% and range of motion over 3 days in patients with acute shoulder tendinopathy. NTG patches improved subjective pain, tendon tenderness, and strength significantly more than placebo at all follow-up points, by 15% to 50% (P<.05 for all comparisons). The study was flawed because the control group started with more pain, tenderness, and weakness than the NTG group. Five patients discontinued NTG because of adverse effects (headache, dermatitis, and facial flushing).

A follow-up study done 5 years after discontinuation of therapy found equal outcomes with NTG and placebo.⁴ Investigators evaluated, by phone or in person, 58 of the 86 patients in the original study. NTG and placebo therapy produced equivalent reductions in subjective 0 to 4 elbow pain scores over baseline (average pain 2.5 initially, 1.5 at 12 weeks, and 1.0 at 5 years; P<.01 for all comparisons with baseline, no significant difference between nitrates and placebo).

Another RCT that evaluated 3 different doses of NTG patches for 8 weeks in 154 patients with chronic lateral epicondylosis found NTG treatment was no better than placebo for pain or strength.⁵ Investigators randomized patients with more than 3 months of symptoms to 3 NTG patch doses (.72 mg/24 h, 1.44 mg/ 24 h, or 3.6 mg/24 h) compared with placebo and evaluated subjective pain (at rest, with activity, and at night), grip strength, and force, at baseline and 8 weeks.

The study lacked a formal wrist strengthening rehabilitation program. Patients in the placebo group had lower baseline pain scores than the NTG groups. Seven patients dropped out of the study because of headaches.

RECOMMENDATIONS

We found no authoritative recommendations regarding the use of topical nitrates for upper extremity tendinopathies.

An online reference text doesn’t make a recommendation, but references the studies described previously.⁶ The authors state that headache is the most common adverse effect of topical nitrates, but it becomes less severe over the course of treatment. They recommend caution in patients with hypotension, pregnancy, or migraines, and those who take diuretics. The authors also note that nitrates are relatively contraindicated in patients with ischemic heart disease, anemia, phosphodiesterase inhibitor therapy (such as sildenafil), angle-closure glaucoma, and allergy to nitrates.

EVIDENCE SUMMARY

A small RCT found that NTG therapy improved short-term pain and joint mobility in patients with acute supraspinatus tendinitis.¹ Investigators randomized 10 men and 10 women with acute shoulder tendonitis (fewer than 7 days’ duration) to use either 5-mg NTG patches or placebo patches daily for 3 days. Patients rated pain on a 10-point scale, and investigators measured joint mobility on a 4-point scale.

After 48 hours of treatment, NTG patches significantly reduced pain ratings from baseline (from 7 to 2 points; P<.001), whereas placebo didn’t (6 vs 6 points; P not significant). NTG patches also improved joint mobility from baseline (from 2 points “moderately restricted” to .1 points “not restricted”; P<.001), but placebo didn’t (1.2 points “mildly restricted” vs 1.2 points; P not significant). The placebo group had less pain and joint restriction than the NTG group at the start of the study. Two patients reported headache 24 hours after starting treatment.

A double-blind RCT evaluating NTG patches for 53 patients (57 shoulders) with chronic supraspinatus tendinopathy (shoulder pain lasting longer than 3 months) found that they improved pain, strength, and range of motion at 3 to 6 months.² Investigators randomized patients to receive one-quarter of a 5-mg 24-hour NTG patch or placebo patch daily and enrolled all patients in a rehabilitation program. They assessed subjective pain (at night and with activity), strength, and external rotation at baseline and at 2, 6, 12, and 24 weeks.

NTG patches improved nighttime pain about 30% (at 12 and 24 weeks), pain with activity about 60% (at 24 weeks), strength about 10% (at 12 and 24 weeks), and range of motion about 20% (at 24 weeks; P<.05 for all comparisons). The placebo group initially had more pain, less strength, and less mobility than the NTG group. Investigators reported no adverse effects.

NTG and rehab improve elbow pain, 
but with side effects


Another RCT comparing topical NTG patches in patients with chronic extensor tendinosis of the elbow found that they improved most parameters.³ Investigators randomized 86 patients with elbow tendonitis (longer than 3 months) to NTG patches (one-quarter of a 5-mg 24-hour patch) or placebo patches and enrolled all patients in a tendon rehabilitation program. They assessed subjective pain, extensor tendon tenderness, and muscle strength at baseline and at 2, 6, 12, and 24 weeks.

Topical nitroglycerin patches improve subjective pain scores by about 30% and range of motion over 3 days in patients with acute shoulder tendinopathy. NTG patches improved subjective pain, tendon tenderness, and strength significantly more than placebo at all follow-up points, by 15% to 50% (P<.05 for all comparisons). The study was flawed because the control group started with more pain, tenderness, and weakness than the NTG group. Five patients discontinued NTG because of adverse effects (headache, dermatitis, and facial flushing).

A follow-up study done 5 years after discontinuation of therapy found equal outcomes with NTG and placebo.⁴ Investigators evaluated, by phone or in person, 58 of the 86 patients in the original study. NTG and placebo therapy produced equivalent reductions in subjective 0 to 4 elbow pain scores over baseline (average pain 2.5 initially, 1.5 at 12 weeks, and 1.0 at 5 years; P<.01 for all comparisons with baseline, no significant difference between nitrates and placebo).

Another RCT that evaluated 3 different doses of NTG patches for 8 weeks in 154 patients with chronic lateral epicondylosis found NTG treatment was no better than placebo for pain or strength.⁵ Investigators randomized patients with more than 3 months of symptoms to 3 NTG patch doses (.72 mg/24 h, 1.44 mg/ 24 h, or 3.6 mg/24 h) compared with placebo and evaluated subjective pain (at rest, with activity, and at night), grip strength, and force, at baseline and 8 weeks.

The study lacked a formal wrist strengthening rehabilitation program. Patients in the placebo group had lower baseline pain scores than the NTG groups. Seven patients dropped out of the study because of headaches.

RECOMMENDATIONS

We found no authoritative recommendations regarding the use of topical nitrates for upper extremity tendinopathies.

An online reference text doesn’t make a recommendation, but references the studies described previously.⁶ The authors state that headache is the most common adverse effect of topical nitrates, but it becomes less severe over the course of treatment. They recommend caution in patients with hypotension, pregnancy, or migraines, and those who take diuretics. The authors also note that nitrates are relatively contraindicated in patients with ischemic heart disease, anemia, phosphodiesterase inhibitor therapy (such as sildenafil), angle-closure glaucoma, and allergy to nitrates.

EVIDENCE SUMMARY

A systematic review and meta-analysis of the effectiveness of oral and topical nucleoside antiviral agents to prevent recurrent HSL in immunocompetent people found 11 RCTs with a total of 1250 patients that compared an active drug against placebo.¹ The medications were topical 5% acyclovir, topical 1% penciclovir, and oral acyclovir, valacyclovir, or famciclovir in various doses. The primary outcome was recurrence of herpes simplex virus type 1 lesions during the treatment period. The relative risk (RR) of recurrence ranged from 0.22 to 1.22. Pooled results found a benefit favoring antiviral agents (RR of recurrence=0.70; 95% confidence interval [CI], 0.55-0.89).

Seven of the trials looked at acyclovir (5 oral, 2 topical). A subgroup analysis demonstrated that oral acyclovir (800-1000 mg/d) was more effective than placebo (RR=0.51; 95% CI, 0.29-0.88), whereas topical acyclovir wasn’t. Oral valacyclovir (2 studies; 500 mg/d for 4 months) also reduced recurrence (RR=0.65; 95% CI, 0.43-0.91). The authors of the meta-analysis noted that although 9 studies favored the use of an antiviral drug, only 4 showed statistically significant differences when compared with placebo, and none of them had a low risk of bias. They concluded that the review supported using oral acyclovir and valacyclovir to prevent recurrent HSL.¹

Oral antivirals produce variable treatment results

Three RCTs evaluated oral antiviral medications against placebo to treat recurrent HSL, with mixed results. The largest RCT found that valacyclovir (2000 mg twice in 24 hours, with or without an additional 1000 mg twice in another 24 hours) modestly but significantly reduced both healing time and duration of pain (by 0.5-0.8 day).² The second RCT showed that a higher, single dose of famciclovir (1500 mg) reduced healing time (by 1.8 days) and pain duration (by 1.2 days) and that a smaller, repeated dose (750 mg twice in 24 hours) reduced healing time alone (by 2.2 days).³

The third RCT demonstrated that acyclovir (400 mg 5 times a day for 5 days) reduced pain duration (by 0.9 day) but didn’t shorten healing time. If acyclovir was started during the prodrome, it decreased the time to disappearance of the lesion’s hard crust (2.1 days’ less time; P=.03), but the clinical significance of this finding is unclear.⁴

Topical treatment shows modest success

Two trials demonstrated that topical acyclovir (5% cream) modestly improved healing time and duration of pain (by as much as half a day). Patients in the first trial (paired RCTs reported together) began treatment within an hour of prodromal symptoms or signs, applying the medication 5 times daily for 4 days.⁵

Topical acyclovir, penciclovir, and docosanol modestly decrease healing time and pain duration—typically by less than a day—and require multiple doses per day.Patients in the second trial used ME-609 cream (5% acyclovir plus 1% hydrocortisone), 5% acyclovir cream, or placebo, all applied 5 times daily for 5 days.⁶ Although the cream with acyclovir and hydrocortisone showed a slight benefit compared with placebo (lessening healing time by 0.8 day and pain duration by 1 day), it didn’t improve healing more than acyclovir alone. Other topical agents (penciclovir 1%; docosanol 10%) produced results similar to topical acyclovir.^7,8

RECOMMENDATIONS

No national guidelines on this topic exist. An online resource notes that most patients don’t require treatment for mild self-limited HSL.⁹ For patients with prodromal symptoms, the authors recommend episodic oral antiviral therapy. Patients who have no prodome but multiple painful or disfiguring lesions may choose to use chronic suppressive therapy with an oral antiviral drug.

EVIDENCE SUMMARY

A systematic review and meta-analysis of the effectiveness of oral and topical nucleoside antiviral agents to prevent recurrent HSL in immunocompetent people found 11 RCTs with a total of 1250 patients that compared an active drug against placebo.¹ The medications were topical 5% acyclovir, topical 1% penciclovir, and oral acyclovir, valacyclovir, or famciclovir in various doses. The primary outcome was recurrence of herpes simplex virus type 1 lesions during the treatment period. The relative risk (RR) of recurrence ranged from 0.22 to 1.22. Pooled results found a benefit favoring antiviral agents (RR of recurrence=0.70; 95% confidence interval [CI], 0.55-0.89).

Seven of the trials looked at acyclovir (5 oral, 2 topical). A subgroup analysis demonstrated that oral acyclovir (800-1000 mg/d) was more effective than placebo (RR=0.51; 95% CI, 0.29-0.88), whereas topical acyclovir wasn’t. Oral valacyclovir (2 studies; 500 mg/d for 4 months) also reduced recurrence (RR=0.65; 95% CI, 0.43-0.91). The authors of the meta-analysis noted that although 9 studies favored the use of an antiviral drug, only 4 showed statistically significant differences when compared with placebo, and none of them had a low risk of bias. They concluded that the review supported using oral acyclovir and valacyclovir to prevent recurrent HSL.¹

Oral antivirals produce variable treatment results

Three RCTs evaluated oral antiviral medications against placebo to treat recurrent HSL, with mixed results. The largest RCT found that valacyclovir (2000 mg twice in 24 hours, with or without an additional 1000 mg twice in another 24 hours) modestly but significantly reduced both healing time and duration of pain (by 0.5-0.8 day).² The second RCT showed that a higher, single dose of famciclovir (1500 mg) reduced healing time (by 1.8 days) and pain duration (by 1.2 days) and that a smaller, repeated dose (750 mg twice in 24 hours) reduced healing time alone (by 2.2 days).³

The third RCT demonstrated that acyclovir (400 mg 5 times a day for 5 days) reduced pain duration (by 0.9 day) but didn’t shorten healing time. If acyclovir was started during the prodrome, it decreased the time to disappearance of the lesion’s hard crust (2.1 days’ less time; P=.03), but the clinical significance of this finding is unclear.⁴

Topical treatment shows modest success

Two trials demonstrated that topical acyclovir (5% cream) modestly improved healing time and duration of pain (by as much as half a day). Patients in the first trial (paired RCTs reported together) began treatment within an hour of prodromal symptoms or signs, applying the medication 5 times daily for 4 days.⁵

Topical acyclovir, penciclovir, and docosanol modestly decrease healing time and pain duration—typically by less than a day—and require multiple doses per day.Patients in the second trial used ME-609 cream (5% acyclovir plus 1% hydrocortisone), 5% acyclovir cream, or placebo, all applied 5 times daily for 5 days.⁶ Although the cream with acyclovir and hydrocortisone showed a slight benefit compared with placebo (lessening healing time by 0.8 day and pain duration by 1 day), it didn’t improve healing more than acyclovir alone. Other topical agents (penciclovir 1%; docosanol 10%) produced results similar to topical acyclovir.^7,8

RECOMMENDATIONS

No national guidelines on this topic exist. An online resource notes that most patients don’t require treatment for mild self-limited HSL.⁹ For patients with prodromal symptoms, the authors recommend episodic oral antiviral therapy. Patients who have no prodome but multiple painful or disfiguring lesions may choose to use chronic suppressive therapy with an oral antiviral drug.

EVIDENCE SUMMARY

A systematic review and meta-analysis of the effectiveness of oral and topical nucleoside antiviral agents to prevent recurrent HSL in immunocompetent people found 11 RCTs with a total of 1250 patients that compared an active drug against placebo.¹ The medications were topical 5% acyclovir, topical 1% penciclovir, and oral acyclovir, valacyclovir, or famciclovir in various doses. The primary outcome was recurrence of herpes simplex virus type 1 lesions during the treatment period. The relative risk (RR) of recurrence ranged from 0.22 to 1.22. Pooled results found a benefit favoring antiviral agents (RR of recurrence=0.70; 95% confidence interval [CI], 0.55-0.89).

Seven of the trials looked at acyclovir (5 oral, 2 topical). A subgroup analysis demonstrated that oral acyclovir (800-1000 mg/d) was more effective than placebo (RR=0.51; 95% CI, 0.29-0.88), whereas topical acyclovir wasn’t. Oral valacyclovir (2 studies; 500 mg/d for 4 months) also reduced recurrence (RR=0.65; 95% CI, 0.43-0.91). The authors of the meta-analysis noted that although 9 studies favored the use of an antiviral drug, only 4 showed statistically significant differences when compared with placebo, and none of them had a low risk of bias. They concluded that the review supported using oral acyclovir and valacyclovir to prevent recurrent HSL.¹

Oral antivirals produce variable treatment results

Three RCTs evaluated oral antiviral medications against placebo to treat recurrent HSL, with mixed results. The largest RCT found that valacyclovir (2000 mg twice in 24 hours, with or without an additional 1000 mg twice in another 24 hours) modestly but significantly reduced both healing time and duration of pain (by 0.5-0.8 day).² The second RCT showed that a higher, single dose of famciclovir (1500 mg) reduced healing time (by 1.8 days) and pain duration (by 1.2 days) and that a smaller, repeated dose (750 mg twice in 24 hours) reduced healing time alone (by 2.2 days).³

The third RCT demonstrated that acyclovir (400 mg 5 times a day for 5 days) reduced pain duration (by 0.9 day) but didn’t shorten healing time. If acyclovir was started during the prodrome, it decreased the time to disappearance of the lesion’s hard crust (2.1 days’ less time; P=.03), but the clinical significance of this finding is unclear.⁴

Topical treatment shows modest success

Two trials demonstrated that topical acyclovir (5% cream) modestly improved healing time and duration of pain (by as much as half a day). Patients in the first trial (paired RCTs reported together) began treatment within an hour of prodromal symptoms or signs, applying the medication 5 times daily for 4 days.⁵

Topical acyclovir, penciclovir, and docosanol modestly decrease healing time and pain duration—typically by less than a day—and require multiple doses per day.Patients in the second trial used ME-609 cream (5% acyclovir plus 1% hydrocortisone), 5% acyclovir cream, or placebo, all applied 5 times daily for 5 days.⁶ Although the cream with acyclovir and hydrocortisone showed a slight benefit compared with placebo (lessening healing time by 0.8 day and pain duration by 1 day), it didn’t improve healing more than acyclovir alone. Other topical agents (penciclovir 1%; docosanol 10%) produced results similar to topical acyclovir.^7,8

RECOMMENDATIONS

No national guidelines on this topic exist. An online resource notes that most patients don’t require treatment for mild self-limited HSL.⁹ For patients with prodromal symptoms, the authors recommend episodic oral antiviral therapy. Patients who have no prodome but multiple painful or disfiguring lesions may choose to use chronic suppressive therapy with an oral antiviral drug.