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Which smoking cessation interventions work best?
NICOTINE REPLACEMENT THERAPY (NRT), bupropion, nortriptyline, clonidine, and varenicline are all effective, although insufficient evidence exists to recommend one intervention over another (SOR: A, systematic reviews).
Effective nonpharmacologic interventions include brief physician advice and more intensive counseling, such as proactive telephone counseling, group and individual counseling, and use of quit lines (SOR: A, systematic reviews).
Evidence summary
NRT. A Cochrane review of 111 randomized controlled trials (RCTs) with a total of >40,000 subjects evaluated abstinence rates after 6 months of NRT and placebo or no treatment.1 All forms of NRT increased abstinence vs placebo or no treatment, independent of setting, duration of treatment, and intensity of nonpharmacologic therapies. Overlapping confidence intervals suggested that no one form of NRT was superior. (The TABLE summarizes all the studies discussed here.)
Bupropion. A Cochrane review of 36 RCTs (N=11,140) showed higher abstinence rates with bupropion than placebo after ≥6 months of follow-up (average quit rate 17% vs 9%). Duration (6 vs 12 months) and intensity (150 vs 300 mg) of therapy didn’t influence the results.2 Six separate RCTs comparing bupropion plus NRT with NRT alone showed significant heterogeneity, but found no significant differences using a mixed-effects model.2
Nortriptyline. A Cochrane review that pooled results from 6 RCTs (N=975) showed superior 6-month abstinence rates for nortriptyline compared with placebo.2 Adding nicotine patches in other RCTs (N=1219) didn’t change abstinence rates.2 No long-term studies have examined other tricyclic antidepressants.
Clonidine. A pooled analysis of 6 RCTs found clonidine superior to placebo after ≥12 weeks of follow-up.3 Results were heavily influenced by one trial limited to heavy smokers and poor tolerability due to adverse effects of therapy, especially sedation and dry mouth.
Nicotine receptor partial agonists and antagonists. Standard dose varenicline was more than twice as likely as placebo to produce abstinence at 6 months in a Cochrane review of 10 RCTs.4 Lower doses were slightly less effective, but had fewer side effects. Adverse effects included mild to moderate nausea and sleep disorders; causation has not been established between varenicline and rare postmarketing reports of severe psychiatric disturbances.4,5
The pooled results of 3 RCTs suggested that varenicline was superior to bupropion, but different abstinence rates for bupropion users in other placebo-controlled trials necessitate caution in interpreting these results.4 Varenicline was not superior to NRT.4
One RCT (N=48) comparing nicotine patches plus the nicotine antagonist mecamylamine with patches plus placebo found improved abstinence rates at 6 and 12 months; a larger RCT didn’t support these findings.6
Table
How effective are smoking cessation interventions?
| Intervention | No. of studies | Effect size* (95% confidence interval) | Total N |
|---|---|---|---|
| NRT vs placebo or no treatment1 | 111 | 1.58 (1.50-1.66) | >40,000 |
| Bupropion vs placebo2 | 36 | 1.69 (1.53-1.85) | 11,140 |
| Bupropion 300 mg/d vs 150 mg/d2 | 3 | 1.08 (0.93-1.26) | 2042 |
| Bupropion + NRT vs NRT2 | 6 | 1.23 (0.67-2.26) | 1106 |
| Nortriptyline vs placebo2 | 6 | 2.03 (1.48-2.78) | 975 |
| Nortriptyline + NRT vs NRT2 | 4 | 1.29 (0.97-1.72) | 1219 |
| Clonidine vs placebo3 | 6 | 1.63 (1.22-2.18) | 776 |
| Varenicline vs placebo, standard dose4 Varenicline vs placebo, low dose4 Varenicline vs bupropion4 Varenicline vs NRT4 | 10 4 3 2 | 2.31 (2.01-2.66) 2.09 (1.56-2.78) 1.52 (1.22-1.88) 1.13 (0.94-1.35) | 4443 1272 1622 778 |
| Mecamylamine + NRT vs NRT+ placebo6 | 1 | 37.5% vs 12.5% | 48 |
| Simple advice vs usual care10-13 | 17 | 1.66 (1.42-1.94) | 15,930 |
| Patient-initiated telephone quit line vs usual care14 | 9 | 1.37 (1.26-1.50) | 24,000 |
| NRT, nicotine replacement therapy. *An effect size >1.0 means that patients using this intervention are more likely not to smoke at 6 to 12 months; larger numbers correlate with greater effectiveness | |||
These interventions are not supported
A review of placebo-controlled RCTs found no evidence of improved abstinence at 6 to 12 months with fluoxetine, paroxetine, sertraline, venlafaxine, citalopram, or monoamine oxidase inhibitors, alone or as adjuncts to NRT.2
No good evidence supports using anxiolytics, silver acetate, Nicobrevin (a nicotine-free smoking cessation aid), lobeline, or naltrexone for smoking cessation.7-9
Simple advice and quit lines help
A Cochrane review of 17 RCTs found that simple advice improved quit rates and maintenance of abstinence at 12 months.10-13
A review of 9 RCTs (N>24,000). found that telephone quit lines increased abstinence, particularly after more than 2 sessions.14
No high-quality studies demonstrate the effectiveness of acupuncture, hypnotherapy, or acupressure for smoking cessation.15,16
Recommendations
The Agency for Health Care Research and Quality recommends counseling (including individual, group, and telephone sessions and brief physician advice) in addition to sustained-release bupropion, NRT, and varenicline as first-line agents. It considers clonidine and nortriptyline second-line therapies.17
1. Silagy C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000146.-
2. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2010;(4):CD000031.-
3. Gourlay SG, Stead LF, Benowitz NL. Clonidine for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000058.-
4. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2011;(2):CD006103.-
5. Product Information for Chantix. New York, NY: Pfizer; 2006.
6. Lancaster T, Stead LF. Mecamylamine for smoking cessation. Cochrane Database Syst Rev. 2009;(1):CD001009.-
7. Hughes JR, Stead LF, Lancaster T. Anxiolytics for smoking cessation. Cochrane Database Syst Rev. 2010;(1):CD002849.-
8. Lancaster T, Stead LF. Silver acetate for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD000191.-
9. David S, Lancaster T, Stead LF, et al. Opioid antagonists for smoking cessation. Cochrane Database Syst Rev. 2009;(4):CD003086.-
10. Lancaster T, Stead LF. Self-help interventions for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001118.-
11. Lancaster T, Stead LF. Physician advice for smoking cessation. Cochrane Database Syst Rev 2008;(2):CD000165.-
12. Lancaster T, Stead LF. Individual behavioral counseling for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD001292.-
13. Stead LF, Lancaster T. Group behavior therapy programs for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001007.-
14. Stead LF, Perera R, Lancaster T. Telephone counseling for smoking cessation. Cochrane Database Syst Rev. 2009;(3):CD002850.-
15. White AR, Rampes H, Campbell JL. Acupuncture and related interventions for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD000009.-
16. Abbot NC, Stead LF, White AR, et al. Hypnotherapy for smoking cessation. Cochrane Database Syst Rev. 2010;(10):CD001008.-
17. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Rockville, MD: US Department of Health and Human Services, Public Health Service; May 2008.
NICOTINE REPLACEMENT THERAPY (NRT), bupropion, nortriptyline, clonidine, and varenicline are all effective, although insufficient evidence exists to recommend one intervention over another (SOR: A, systematic reviews).
Effective nonpharmacologic interventions include brief physician advice and more intensive counseling, such as proactive telephone counseling, group and individual counseling, and use of quit lines (SOR: A, systematic reviews).
Evidence summary
NRT. A Cochrane review of 111 randomized controlled trials (RCTs) with a total of >40,000 subjects evaluated abstinence rates after 6 months of NRT and placebo or no treatment.1 All forms of NRT increased abstinence vs placebo or no treatment, independent of setting, duration of treatment, and intensity of nonpharmacologic therapies. Overlapping confidence intervals suggested that no one form of NRT was superior. (The TABLE summarizes all the studies discussed here.)
Bupropion. A Cochrane review of 36 RCTs (N=11,140) showed higher abstinence rates with bupropion than placebo after ≥6 months of follow-up (average quit rate 17% vs 9%). Duration (6 vs 12 months) and intensity (150 vs 300 mg) of therapy didn’t influence the results.2 Six separate RCTs comparing bupropion plus NRT with NRT alone showed significant heterogeneity, but found no significant differences using a mixed-effects model.2
Nortriptyline. A Cochrane review that pooled results from 6 RCTs (N=975) showed superior 6-month abstinence rates for nortriptyline compared with placebo.2 Adding nicotine patches in other RCTs (N=1219) didn’t change abstinence rates.2 No long-term studies have examined other tricyclic antidepressants.
Clonidine. A pooled analysis of 6 RCTs found clonidine superior to placebo after ≥12 weeks of follow-up.3 Results were heavily influenced by one trial limited to heavy smokers and poor tolerability due to adverse effects of therapy, especially sedation and dry mouth.
Nicotine receptor partial agonists and antagonists. Standard dose varenicline was more than twice as likely as placebo to produce abstinence at 6 months in a Cochrane review of 10 RCTs.4 Lower doses were slightly less effective, but had fewer side effects. Adverse effects included mild to moderate nausea and sleep disorders; causation has not been established between varenicline and rare postmarketing reports of severe psychiatric disturbances.4,5
The pooled results of 3 RCTs suggested that varenicline was superior to bupropion, but different abstinence rates for bupropion users in other placebo-controlled trials necessitate caution in interpreting these results.4 Varenicline was not superior to NRT.4
One RCT (N=48) comparing nicotine patches plus the nicotine antagonist mecamylamine with patches plus placebo found improved abstinence rates at 6 and 12 months; a larger RCT didn’t support these findings.6
Table
How effective are smoking cessation interventions?
| Intervention | No. of studies | Effect size* (95% confidence interval) | Total N |
|---|---|---|---|
| NRT vs placebo or no treatment1 | 111 | 1.58 (1.50-1.66) | >40,000 |
| Bupropion vs placebo2 | 36 | 1.69 (1.53-1.85) | 11,140 |
| Bupropion 300 mg/d vs 150 mg/d2 | 3 | 1.08 (0.93-1.26) | 2042 |
| Bupropion + NRT vs NRT2 | 6 | 1.23 (0.67-2.26) | 1106 |
| Nortriptyline vs placebo2 | 6 | 2.03 (1.48-2.78) | 975 |
| Nortriptyline + NRT vs NRT2 | 4 | 1.29 (0.97-1.72) | 1219 |
| Clonidine vs placebo3 | 6 | 1.63 (1.22-2.18) | 776 |
| Varenicline vs placebo, standard dose4 Varenicline vs placebo, low dose4 Varenicline vs bupropion4 Varenicline vs NRT4 | 10 4 3 2 | 2.31 (2.01-2.66) 2.09 (1.56-2.78) 1.52 (1.22-1.88) 1.13 (0.94-1.35) | 4443 1272 1622 778 |
| Mecamylamine + NRT vs NRT+ placebo6 | 1 | 37.5% vs 12.5% | 48 |
| Simple advice vs usual care10-13 | 17 | 1.66 (1.42-1.94) | 15,930 |
| Patient-initiated telephone quit line vs usual care14 | 9 | 1.37 (1.26-1.50) | 24,000 |
| NRT, nicotine replacement therapy. *An effect size >1.0 means that patients using this intervention are more likely not to smoke at 6 to 12 months; larger numbers correlate with greater effectiveness | |||
These interventions are not supported
A review of placebo-controlled RCTs found no evidence of improved abstinence at 6 to 12 months with fluoxetine, paroxetine, sertraline, venlafaxine, citalopram, or monoamine oxidase inhibitors, alone or as adjuncts to NRT.2
No good evidence supports using anxiolytics, silver acetate, Nicobrevin (a nicotine-free smoking cessation aid), lobeline, or naltrexone for smoking cessation.7-9
Simple advice and quit lines help
A Cochrane review of 17 RCTs found that simple advice improved quit rates and maintenance of abstinence at 12 months.10-13
A review of 9 RCTs (N>24,000). found that telephone quit lines increased abstinence, particularly after more than 2 sessions.14
No high-quality studies demonstrate the effectiveness of acupuncture, hypnotherapy, or acupressure for smoking cessation.15,16
Recommendations
The Agency for Health Care Research and Quality recommends counseling (including individual, group, and telephone sessions and brief physician advice) in addition to sustained-release bupropion, NRT, and varenicline as first-line agents. It considers clonidine and nortriptyline second-line therapies.17
NICOTINE REPLACEMENT THERAPY (NRT), bupropion, nortriptyline, clonidine, and varenicline are all effective, although insufficient evidence exists to recommend one intervention over another (SOR: A, systematic reviews).
Effective nonpharmacologic interventions include brief physician advice and more intensive counseling, such as proactive telephone counseling, group and individual counseling, and use of quit lines (SOR: A, systematic reviews).
Evidence summary
NRT. A Cochrane review of 111 randomized controlled trials (RCTs) with a total of >40,000 subjects evaluated abstinence rates after 6 months of NRT and placebo or no treatment.1 All forms of NRT increased abstinence vs placebo or no treatment, independent of setting, duration of treatment, and intensity of nonpharmacologic therapies. Overlapping confidence intervals suggested that no one form of NRT was superior. (The TABLE summarizes all the studies discussed here.)
Bupropion. A Cochrane review of 36 RCTs (N=11,140) showed higher abstinence rates with bupropion than placebo after ≥6 months of follow-up (average quit rate 17% vs 9%). Duration (6 vs 12 months) and intensity (150 vs 300 mg) of therapy didn’t influence the results.2 Six separate RCTs comparing bupropion plus NRT with NRT alone showed significant heterogeneity, but found no significant differences using a mixed-effects model.2
Nortriptyline. A Cochrane review that pooled results from 6 RCTs (N=975) showed superior 6-month abstinence rates for nortriptyline compared with placebo.2 Adding nicotine patches in other RCTs (N=1219) didn’t change abstinence rates.2 No long-term studies have examined other tricyclic antidepressants.
Clonidine. A pooled analysis of 6 RCTs found clonidine superior to placebo after ≥12 weeks of follow-up.3 Results were heavily influenced by one trial limited to heavy smokers and poor tolerability due to adverse effects of therapy, especially sedation and dry mouth.
Nicotine receptor partial agonists and antagonists. Standard dose varenicline was more than twice as likely as placebo to produce abstinence at 6 months in a Cochrane review of 10 RCTs.4 Lower doses were slightly less effective, but had fewer side effects. Adverse effects included mild to moderate nausea and sleep disorders; causation has not been established between varenicline and rare postmarketing reports of severe psychiatric disturbances.4,5
The pooled results of 3 RCTs suggested that varenicline was superior to bupropion, but different abstinence rates for bupropion users in other placebo-controlled trials necessitate caution in interpreting these results.4 Varenicline was not superior to NRT.4
One RCT (N=48) comparing nicotine patches plus the nicotine antagonist mecamylamine with patches plus placebo found improved abstinence rates at 6 and 12 months; a larger RCT didn’t support these findings.6
Table
How effective are smoking cessation interventions?
| Intervention | No. of studies | Effect size* (95% confidence interval) | Total N |
|---|---|---|---|
| NRT vs placebo or no treatment1 | 111 | 1.58 (1.50-1.66) | >40,000 |
| Bupropion vs placebo2 | 36 | 1.69 (1.53-1.85) | 11,140 |
| Bupropion 300 mg/d vs 150 mg/d2 | 3 | 1.08 (0.93-1.26) | 2042 |
| Bupropion + NRT vs NRT2 | 6 | 1.23 (0.67-2.26) | 1106 |
| Nortriptyline vs placebo2 | 6 | 2.03 (1.48-2.78) | 975 |
| Nortriptyline + NRT vs NRT2 | 4 | 1.29 (0.97-1.72) | 1219 |
| Clonidine vs placebo3 | 6 | 1.63 (1.22-2.18) | 776 |
| Varenicline vs placebo, standard dose4 Varenicline vs placebo, low dose4 Varenicline vs bupropion4 Varenicline vs NRT4 | 10 4 3 2 | 2.31 (2.01-2.66) 2.09 (1.56-2.78) 1.52 (1.22-1.88) 1.13 (0.94-1.35) | 4443 1272 1622 778 |
| Mecamylamine + NRT vs NRT+ placebo6 | 1 | 37.5% vs 12.5% | 48 |
| Simple advice vs usual care10-13 | 17 | 1.66 (1.42-1.94) | 15,930 |
| Patient-initiated telephone quit line vs usual care14 | 9 | 1.37 (1.26-1.50) | 24,000 |
| NRT, nicotine replacement therapy. *An effect size >1.0 means that patients using this intervention are more likely not to smoke at 6 to 12 months; larger numbers correlate with greater effectiveness | |||
These interventions are not supported
A review of placebo-controlled RCTs found no evidence of improved abstinence at 6 to 12 months with fluoxetine, paroxetine, sertraline, venlafaxine, citalopram, or monoamine oxidase inhibitors, alone or as adjuncts to NRT.2
No good evidence supports using anxiolytics, silver acetate, Nicobrevin (a nicotine-free smoking cessation aid), lobeline, or naltrexone for smoking cessation.7-9
Simple advice and quit lines help
A Cochrane review of 17 RCTs found that simple advice improved quit rates and maintenance of abstinence at 12 months.10-13
A review of 9 RCTs (N>24,000). found that telephone quit lines increased abstinence, particularly after more than 2 sessions.14
No high-quality studies demonstrate the effectiveness of acupuncture, hypnotherapy, or acupressure for smoking cessation.15,16
Recommendations
The Agency for Health Care Research and Quality recommends counseling (including individual, group, and telephone sessions and brief physician advice) in addition to sustained-release bupropion, NRT, and varenicline as first-line agents. It considers clonidine and nortriptyline second-line therapies.17
1. Silagy C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000146.-
2. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2010;(4):CD000031.-
3. Gourlay SG, Stead LF, Benowitz NL. Clonidine for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000058.-
4. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2011;(2):CD006103.-
5. Product Information for Chantix. New York, NY: Pfizer; 2006.
6. Lancaster T, Stead LF. Mecamylamine for smoking cessation. Cochrane Database Syst Rev. 2009;(1):CD001009.-
7. Hughes JR, Stead LF, Lancaster T. Anxiolytics for smoking cessation. Cochrane Database Syst Rev. 2010;(1):CD002849.-
8. Lancaster T, Stead LF. Silver acetate for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD000191.-
9. David S, Lancaster T, Stead LF, et al. Opioid antagonists for smoking cessation. Cochrane Database Syst Rev. 2009;(4):CD003086.-
10. Lancaster T, Stead LF. Self-help interventions for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001118.-
11. Lancaster T, Stead LF. Physician advice for smoking cessation. Cochrane Database Syst Rev 2008;(2):CD000165.-
12. Lancaster T, Stead LF. Individual behavioral counseling for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD001292.-
13. Stead LF, Lancaster T. Group behavior therapy programs for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001007.-
14. Stead LF, Perera R, Lancaster T. Telephone counseling for smoking cessation. Cochrane Database Syst Rev. 2009;(3):CD002850.-
15. White AR, Rampes H, Campbell JL. Acupuncture and related interventions for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD000009.-
16. Abbot NC, Stead LF, White AR, et al. Hypnotherapy for smoking cessation. Cochrane Database Syst Rev. 2010;(10):CD001008.-
17. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Rockville, MD: US Department of Health and Human Services, Public Health Service; May 2008.
1. Silagy C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000146.-
2. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2010;(4):CD000031.-
3. Gourlay SG, Stead LF, Benowitz NL. Clonidine for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000058.-
4. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2011;(2):CD006103.-
5. Product Information for Chantix. New York, NY: Pfizer; 2006.
6. Lancaster T, Stead LF. Mecamylamine for smoking cessation. Cochrane Database Syst Rev. 2009;(1):CD001009.-
7. Hughes JR, Stead LF, Lancaster T. Anxiolytics for smoking cessation. Cochrane Database Syst Rev. 2010;(1):CD002849.-
8. Lancaster T, Stead LF. Silver acetate for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD000191.-
9. David S, Lancaster T, Stead LF, et al. Opioid antagonists for smoking cessation. Cochrane Database Syst Rev. 2009;(4):CD003086.-
10. Lancaster T, Stead LF. Self-help interventions for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001118.-
11. Lancaster T, Stead LF. Physician advice for smoking cessation. Cochrane Database Syst Rev 2008;(2):CD000165.-
12. Lancaster T, Stead LF. Individual behavioral counseling for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD001292.-
13. Stead LF, Lancaster T. Group behavior therapy programs for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001007.-
14. Stead LF, Perera R, Lancaster T. Telephone counseling for smoking cessation. Cochrane Database Syst Rev. 2009;(3):CD002850.-
15. White AR, Rampes H, Campbell JL. Acupuncture and related interventions for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD000009.-
16. Abbot NC, Stead LF, White AR, et al. Hypnotherapy for smoking cessation. Cochrane Database Syst Rev. 2010;(10):CD001008.-
17. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Rockville, MD: US Department of Health and Human Services, Public Health Service; May 2008.
Evidence-based answers from the Family Physicians Inquiries Network
How should we use the coronary artery calcium score to predict cardiovascular risk?
THE CORONARY ARTERY CALCIUM (CAC) SCORE—an independent predictor of cardiovascular events (strength of recommendation [SOR]: C, systematic review of disease-oriented outcomes)—can be used, in addition to traditional risk factor assessment, to further stratify the risk of coronary heart disease (CHD) in asymptomatic patients (SOR: C, multiple large observational studies with disease-oriented outcomes).
Although a high CAC score is associated with a greater risk of cardiovascular disease, no studies have evaluated cardiovascular outcomes of CAC-guided treatment, so its value remains theoretical.
Evidence summary
Most atherosclerotic lesions are calcified. The degree of calcification is proportional to the severity of atherosclerosis and can be quantified by the CAC score as measured by electron beam computed tomography (EBCT).1
As the CAC score rises, so does risk
A systematic review of 9 studies evaluated the relationship between CAC scores and coronary artery disease (CAD) in asymptomatic patients (TABLE). CAD was measured by such clinical outcomes as unstable angina, myocardial infarction, stroke, coronary death, all-cause mortality, or need for revascularization. The relative risk of CAD for a moderate CAC score compared with a low score was 3.5 (95% confidence interval [CI], 2.4-5.1) and for a high score compared with a low score was 9.9 (95% CI, 5.3-17.6). Some of the studies were of poor quality, including self-referred patients, for example.2
A subsequent study found similar associations. The observational study of 25,253 asymptomatic individuals referred for CAC testing to assess cardiovascular risk demonstrated that CAC was an independent predictor of all-cause mortality. After a mean of 6.8 years, the adjusted relative risk increased incrementally from 1.48 (95% CI, 0.71-3.07) for a CAC score of 1 to 10, to 9.36 (95% CI, 5.36-16.33) for a score ≥1,000, compared with a score of 0.3
Table
What does that CAC score mean?1
| Score | Severity of disease |
|---|---|
| <1 | No identifiable disease |
| 1-10 | Mild |
| 11-100 | Moderate |
| 101-400 | Moderate to high |
| >400 | Severe |
| CAC, coronary artery calcium. | |
CAC predicts risk, but does it improve treatment or outcomes?
Analysis of 3201 women followed for an average of 3.75 years in the Multi-Ethnic Study of Atherosclerosis cohort revealed that women at low Framingham risk, but with detectable CAC, had an increased risk of CHD (hazard ratio [HR]=6.5; 95% CI, 2.6-16.4) and cardiovascular disease events (HR=5.2; 95% CI, 2.5-10.8).4
The St. Francis Heart Study prospectively compared CAC with standard CHD risk factors for predicting atherosclerotic cardiovascular disease (ASCVD) events in 4903 asymptomatic people between 50 and 70 years of age. For CAC scores ≥100 compared with scores <100, relative risk was 9.6 (95% CI, 6.7-13.9) for all ASCVD events, 11.1 (95% CI, 7.3-16.7) for all CHD events, and 9.2 (95% CI, 4.9-17.3) for nonfatal myocardial infarction and death. The CAC score predicted CHD events more accurately than standard risk factors and reclassified 24% of intermediate-risk women and 17% of intermediate-risk men into a higher-risk group.5
Despite studies that correlate higher CAC score with increased cardiovascular risk, we found no evidence that testing leads to improved treatment for preventing CHD or better cardiovascular outcomes.
Recommendations
The American College of Cardiology suggests that measuring CAC may be reasonable for asymptomatic patients with intermediate CHD risk (10%-20% 10-year risk of CHD events), for whom elevated CAC scores could lead to a higher-risk classification and subsequent modification of management.6 The College doesn’t recommend evaluating CAC in patients with low CHD risk, because it would constitute screening the general population, or asymptomatic patients with high CHD risk, who are already candidates for intensive risk modification.
The US Preventive Services Task Force conducted its own review and concluded that although the CAC score is an independent predictor of major CHD events, insufficient evidence exists to support its use to further stratify risk in intermediate-risk patients.7
1. Rumberger JA, Brundage BH, Rader DJ, et al. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin Proc. 1999;74:243-252.
2. Dendukuri N, Chiu K, Brophy JM. Validity of electron beam computed tomography for coronary artery disease: a systematic review and meta-analysis. BMC Med. 2007;5:35.-
3. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. J Am Coll Cardiol. 2007;49:1860-1870.
4. Lakoski SG, Greenland P, Wong N, et al. Coronary artery calcium scores and risk for cardiovascular events in women classified as “low risk” based on Framingham risk score: the multi-ethnic study of atherosclerosis (MESA). Arch Intern Med. 2007;167:2437-2442.
5. Arad Y, Goodman KJ, Roth M, et al. Coronary calcification, coronary disease risk factors, creactive protein, and atherosclerotic cardiovascular disease events. J Am Coll Cardiol. 2005;46:158-165.
6. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document of Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2007;49:378-402.
7. US Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;151:474-482.
THE CORONARY ARTERY CALCIUM (CAC) SCORE—an independent predictor of cardiovascular events (strength of recommendation [SOR]: C, systematic review of disease-oriented outcomes)—can be used, in addition to traditional risk factor assessment, to further stratify the risk of coronary heart disease (CHD) in asymptomatic patients (SOR: C, multiple large observational studies with disease-oriented outcomes).
Although a high CAC score is associated with a greater risk of cardiovascular disease, no studies have evaluated cardiovascular outcomes of CAC-guided treatment, so its value remains theoretical.
Evidence summary
Most atherosclerotic lesions are calcified. The degree of calcification is proportional to the severity of atherosclerosis and can be quantified by the CAC score as measured by electron beam computed tomography (EBCT).1
As the CAC score rises, so does risk
A systematic review of 9 studies evaluated the relationship between CAC scores and coronary artery disease (CAD) in asymptomatic patients (TABLE). CAD was measured by such clinical outcomes as unstable angina, myocardial infarction, stroke, coronary death, all-cause mortality, or need for revascularization. The relative risk of CAD for a moderate CAC score compared with a low score was 3.5 (95% confidence interval [CI], 2.4-5.1) and for a high score compared with a low score was 9.9 (95% CI, 5.3-17.6). Some of the studies were of poor quality, including self-referred patients, for example.2
A subsequent study found similar associations. The observational study of 25,253 asymptomatic individuals referred for CAC testing to assess cardiovascular risk demonstrated that CAC was an independent predictor of all-cause mortality. After a mean of 6.8 years, the adjusted relative risk increased incrementally from 1.48 (95% CI, 0.71-3.07) for a CAC score of 1 to 10, to 9.36 (95% CI, 5.36-16.33) for a score ≥1,000, compared with a score of 0.3
Table
What does that CAC score mean?1
| Score | Severity of disease |
|---|---|
| <1 | No identifiable disease |
| 1-10 | Mild |
| 11-100 | Moderate |
| 101-400 | Moderate to high |
| >400 | Severe |
| CAC, coronary artery calcium. | |
CAC predicts risk, but does it improve treatment or outcomes?
Analysis of 3201 women followed for an average of 3.75 years in the Multi-Ethnic Study of Atherosclerosis cohort revealed that women at low Framingham risk, but with detectable CAC, had an increased risk of CHD (hazard ratio [HR]=6.5; 95% CI, 2.6-16.4) and cardiovascular disease events (HR=5.2; 95% CI, 2.5-10.8).4
The St. Francis Heart Study prospectively compared CAC with standard CHD risk factors for predicting atherosclerotic cardiovascular disease (ASCVD) events in 4903 asymptomatic people between 50 and 70 years of age. For CAC scores ≥100 compared with scores <100, relative risk was 9.6 (95% CI, 6.7-13.9) for all ASCVD events, 11.1 (95% CI, 7.3-16.7) for all CHD events, and 9.2 (95% CI, 4.9-17.3) for nonfatal myocardial infarction and death. The CAC score predicted CHD events more accurately than standard risk factors and reclassified 24% of intermediate-risk women and 17% of intermediate-risk men into a higher-risk group.5
Despite studies that correlate higher CAC score with increased cardiovascular risk, we found no evidence that testing leads to improved treatment for preventing CHD or better cardiovascular outcomes.
Recommendations
The American College of Cardiology suggests that measuring CAC may be reasonable for asymptomatic patients with intermediate CHD risk (10%-20% 10-year risk of CHD events), for whom elevated CAC scores could lead to a higher-risk classification and subsequent modification of management.6 The College doesn’t recommend evaluating CAC in patients with low CHD risk, because it would constitute screening the general population, or asymptomatic patients with high CHD risk, who are already candidates for intensive risk modification.
The US Preventive Services Task Force conducted its own review and concluded that although the CAC score is an independent predictor of major CHD events, insufficient evidence exists to support its use to further stratify risk in intermediate-risk patients.7
THE CORONARY ARTERY CALCIUM (CAC) SCORE—an independent predictor of cardiovascular events (strength of recommendation [SOR]: C, systematic review of disease-oriented outcomes)—can be used, in addition to traditional risk factor assessment, to further stratify the risk of coronary heart disease (CHD) in asymptomatic patients (SOR: C, multiple large observational studies with disease-oriented outcomes).
Although a high CAC score is associated with a greater risk of cardiovascular disease, no studies have evaluated cardiovascular outcomes of CAC-guided treatment, so its value remains theoretical.
Evidence summary
Most atherosclerotic lesions are calcified. The degree of calcification is proportional to the severity of atherosclerosis and can be quantified by the CAC score as measured by electron beam computed tomography (EBCT).1
As the CAC score rises, so does risk
A systematic review of 9 studies evaluated the relationship between CAC scores and coronary artery disease (CAD) in asymptomatic patients (TABLE). CAD was measured by such clinical outcomes as unstable angina, myocardial infarction, stroke, coronary death, all-cause mortality, or need for revascularization. The relative risk of CAD for a moderate CAC score compared with a low score was 3.5 (95% confidence interval [CI], 2.4-5.1) and for a high score compared with a low score was 9.9 (95% CI, 5.3-17.6). Some of the studies were of poor quality, including self-referred patients, for example.2
A subsequent study found similar associations. The observational study of 25,253 asymptomatic individuals referred for CAC testing to assess cardiovascular risk demonstrated that CAC was an independent predictor of all-cause mortality. After a mean of 6.8 years, the adjusted relative risk increased incrementally from 1.48 (95% CI, 0.71-3.07) for a CAC score of 1 to 10, to 9.36 (95% CI, 5.36-16.33) for a score ≥1,000, compared with a score of 0.3
Table
What does that CAC score mean?1
| Score | Severity of disease |
|---|---|
| <1 | No identifiable disease |
| 1-10 | Mild |
| 11-100 | Moderate |
| 101-400 | Moderate to high |
| >400 | Severe |
| CAC, coronary artery calcium. | |
CAC predicts risk, but does it improve treatment or outcomes?
Analysis of 3201 women followed for an average of 3.75 years in the Multi-Ethnic Study of Atherosclerosis cohort revealed that women at low Framingham risk, but with detectable CAC, had an increased risk of CHD (hazard ratio [HR]=6.5; 95% CI, 2.6-16.4) and cardiovascular disease events (HR=5.2; 95% CI, 2.5-10.8).4
The St. Francis Heart Study prospectively compared CAC with standard CHD risk factors for predicting atherosclerotic cardiovascular disease (ASCVD) events in 4903 asymptomatic people between 50 and 70 years of age. For CAC scores ≥100 compared with scores <100, relative risk was 9.6 (95% CI, 6.7-13.9) for all ASCVD events, 11.1 (95% CI, 7.3-16.7) for all CHD events, and 9.2 (95% CI, 4.9-17.3) for nonfatal myocardial infarction and death. The CAC score predicted CHD events more accurately than standard risk factors and reclassified 24% of intermediate-risk women and 17% of intermediate-risk men into a higher-risk group.5
Despite studies that correlate higher CAC score with increased cardiovascular risk, we found no evidence that testing leads to improved treatment for preventing CHD or better cardiovascular outcomes.
Recommendations
The American College of Cardiology suggests that measuring CAC may be reasonable for asymptomatic patients with intermediate CHD risk (10%-20% 10-year risk of CHD events), for whom elevated CAC scores could lead to a higher-risk classification and subsequent modification of management.6 The College doesn’t recommend evaluating CAC in patients with low CHD risk, because it would constitute screening the general population, or asymptomatic patients with high CHD risk, who are already candidates for intensive risk modification.
The US Preventive Services Task Force conducted its own review and concluded that although the CAC score is an independent predictor of major CHD events, insufficient evidence exists to support its use to further stratify risk in intermediate-risk patients.7
1. Rumberger JA, Brundage BH, Rader DJ, et al. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin Proc. 1999;74:243-252.
2. Dendukuri N, Chiu K, Brophy JM. Validity of electron beam computed tomography for coronary artery disease: a systematic review and meta-analysis. BMC Med. 2007;5:35.-
3. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. J Am Coll Cardiol. 2007;49:1860-1870.
4. Lakoski SG, Greenland P, Wong N, et al. Coronary artery calcium scores and risk for cardiovascular events in women classified as “low risk” based on Framingham risk score: the multi-ethnic study of atherosclerosis (MESA). Arch Intern Med. 2007;167:2437-2442.
5. Arad Y, Goodman KJ, Roth M, et al. Coronary calcification, coronary disease risk factors, creactive protein, and atherosclerotic cardiovascular disease events. J Am Coll Cardiol. 2005;46:158-165.
6. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document of Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2007;49:378-402.
7. US Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;151:474-482.
1. Rumberger JA, Brundage BH, Rader DJ, et al. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin Proc. 1999;74:243-252.
2. Dendukuri N, Chiu K, Brophy JM. Validity of electron beam computed tomography for coronary artery disease: a systematic review and meta-analysis. BMC Med. 2007;5:35.-
3. Budoff MJ, Shaw LJ, Liu ST, et al. Long-term prognosis associated with coronary calcification: observations from a registry of 25,253 patients. J Am Coll Cardiol. 2007;49:1860-1870.
4. Lakoski SG, Greenland P, Wong N, et al. Coronary artery calcium scores and risk for cardiovascular events in women classified as “low risk” based on Framingham risk score: the multi-ethnic study of atherosclerosis (MESA). Arch Intern Med. 2007;167:2437-2442.
5. Arad Y, Goodman KJ, Roth M, et al. Coronary calcification, coronary disease risk factors, creactive protein, and atherosclerotic cardiovascular disease events. J Am Coll Cardiol. 2005;46:158-165.
6. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document of Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2007;49:378-402.
7. US Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2009;151:474-482.
Evidence-based answers from the Family Physicians Inquiries Network
What is the long-term educational outlook for youngsters with ADHD?
CHILDREN AND ADOLESCENTS with attention deficit hyperactivity disorder (ADHD) complete fewer years of school, graduate from high school at a lower rate, and are less likely to enroll in graduate school. Older adolescents and young adults with ADHD tend to underperform in both educational and occupational settings (strength of recommendation: A, 2 prospective cohort studies and a case control study).
These findings are based solely on patients with ADHD who were referred to psychiatric clinics and therefore may reflect a more severe spectrum of ADHD effects.
Evidence summary
A prospective cohort study compared educational and employment outcomes among 91 middle-class white boys, 6 to 12 years of age, with ADHD who were referred to a psychiatric clinic with outcomes for 96 matched controls. Investigators used multiple educational achievement tests to evaluate participants when they enrolled in the study, then administered educational and occupational questionnaires 16 years later.
Boys with ADHD completed 2.5 fewer years of school than controls (P=.001). Although rates of employment for the 2 groups were the same at 90%, those with ADHD had a significantly poorer occupational ranking than controls using the Hollingshead and Redlich system, which rates occupations on 7-point scale, with 1 representing top-ranked occupations. Individuals with ADHD scored 4.4 points compared with 3.5 points for the control group (P<.001). However, by the end of the study, more individuals with ADHD owned and operated their own businesses compared with controls (18% vs 5%; P<.01).1
Fewer degrees but comparable employment rates
A similar prospective cohort study evaluated educational and occupational outcomes among 104 boys with ADHD and 106 controls. Investigators recruited boys 5 to 11 years of age from a psychiatric research clinic and followed them for a mean of 17 years using educational and occupational questionnaires.
Boys with ADHD completed 2 fewer years of school than controls (P=.0001), and more boys in the ADHD group failed to complete high school (25% vs 1%; P value not supplied). Fewer individuals with ADHD than controls obtained a bachelor’s degree (15% vs 50%; P<.001), and fewer enrolled in graduate school (3% vs 16%; P value not given). Employment was comparable in the 2 groups, however (92% vs 93%, P=.07).2
Less success in school and at work
Another prospective case-control study also found that people with ADHD achieved less educational and occupational success than controls. The study compared 224 subjects between 18 and 55 years of age with ADHD from a psychiatric referral clinic with 146 controls matched for age and intelligence quotient (IQ). Investigators correlated predicted educational achievement based on IQ in the controls with that observed in subjects with ADHD.
Five years later, subjects with ADHD didn’t perform as well as predicted. Fewer earned college degrees (29% vs 52%) or graduate degrees (20% vs 33%), and more earned no college or graduate school degrees (50% vs 16%) (P<.001 for comparison of observed compared with expected means using Wilcoxon matched pairs test). Similarly, fewer subjects with ADHD attained a level of 6 on the Hollingshead Socioeconomic Status Scale than controls (58% vs 80%; P<.001).3
Recommendations
We found no statements from national organizations about the long-term educational prognosis for children and adolescents with ADHD. However, the authors of the Multimodal Treatment Study of Children with ADHD have expressed the opinion that prognosis depends on initial presentation (including severity of symptoms and comorbid conduct disorders), intellect, social advantage, and response to treatment.4
1. Mannuzza S, Klein RG, Bessler A, et al. Adult outcome of hyperactive boys: educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry. 1993;50:565-576.
2. Mannuzza S, Klein RG, Bessler A, et al. Educational and occupational outcome of hyperactive boys grown up. J Am Acad Child Adolesc Psychiatry. 1997;36:1222-1227.
3. Biederman J, Petty CR, Fried R, et al. Educational and occupational underattainment in adults with attention-deficit/hyperactivity disorder: a controlled study. J Clin Psychiatry. 2008;69:1217-1222.
4. Molina BS, Hinshaw SP, Swanson JM, et al. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry. 2009;48:484-500.
CHILDREN AND ADOLESCENTS with attention deficit hyperactivity disorder (ADHD) complete fewer years of school, graduate from high school at a lower rate, and are less likely to enroll in graduate school. Older adolescents and young adults with ADHD tend to underperform in both educational and occupational settings (strength of recommendation: A, 2 prospective cohort studies and a case control study).
These findings are based solely on patients with ADHD who were referred to psychiatric clinics and therefore may reflect a more severe spectrum of ADHD effects.
Evidence summary
A prospective cohort study compared educational and employment outcomes among 91 middle-class white boys, 6 to 12 years of age, with ADHD who were referred to a psychiatric clinic with outcomes for 96 matched controls. Investigators used multiple educational achievement tests to evaluate participants when they enrolled in the study, then administered educational and occupational questionnaires 16 years later.
Boys with ADHD completed 2.5 fewer years of school than controls (P=.001). Although rates of employment for the 2 groups were the same at 90%, those with ADHD had a significantly poorer occupational ranking than controls using the Hollingshead and Redlich system, which rates occupations on 7-point scale, with 1 representing top-ranked occupations. Individuals with ADHD scored 4.4 points compared with 3.5 points for the control group (P<.001). However, by the end of the study, more individuals with ADHD owned and operated their own businesses compared with controls (18% vs 5%; P<.01).1
Fewer degrees but comparable employment rates
A similar prospective cohort study evaluated educational and occupational outcomes among 104 boys with ADHD and 106 controls. Investigators recruited boys 5 to 11 years of age from a psychiatric research clinic and followed them for a mean of 17 years using educational and occupational questionnaires.
Boys with ADHD completed 2 fewer years of school than controls (P=.0001), and more boys in the ADHD group failed to complete high school (25% vs 1%; P value not supplied). Fewer individuals with ADHD than controls obtained a bachelor’s degree (15% vs 50%; P<.001), and fewer enrolled in graduate school (3% vs 16%; P value not given). Employment was comparable in the 2 groups, however (92% vs 93%, P=.07).2
Less success in school and at work
Another prospective case-control study also found that people with ADHD achieved less educational and occupational success than controls. The study compared 224 subjects between 18 and 55 years of age with ADHD from a psychiatric referral clinic with 146 controls matched for age and intelligence quotient (IQ). Investigators correlated predicted educational achievement based on IQ in the controls with that observed in subjects with ADHD.
Five years later, subjects with ADHD didn’t perform as well as predicted. Fewer earned college degrees (29% vs 52%) or graduate degrees (20% vs 33%), and more earned no college or graduate school degrees (50% vs 16%) (P<.001 for comparison of observed compared with expected means using Wilcoxon matched pairs test). Similarly, fewer subjects with ADHD attained a level of 6 on the Hollingshead Socioeconomic Status Scale than controls (58% vs 80%; P<.001).3
Recommendations
We found no statements from national organizations about the long-term educational prognosis for children and adolescents with ADHD. However, the authors of the Multimodal Treatment Study of Children with ADHD have expressed the opinion that prognosis depends on initial presentation (including severity of symptoms and comorbid conduct disorders), intellect, social advantage, and response to treatment.4
CHILDREN AND ADOLESCENTS with attention deficit hyperactivity disorder (ADHD) complete fewer years of school, graduate from high school at a lower rate, and are less likely to enroll in graduate school. Older adolescents and young adults with ADHD tend to underperform in both educational and occupational settings (strength of recommendation: A, 2 prospective cohort studies and a case control study).
These findings are based solely on patients with ADHD who were referred to psychiatric clinics and therefore may reflect a more severe spectrum of ADHD effects.
Evidence summary
A prospective cohort study compared educational and employment outcomes among 91 middle-class white boys, 6 to 12 years of age, with ADHD who were referred to a psychiatric clinic with outcomes for 96 matched controls. Investigators used multiple educational achievement tests to evaluate participants when they enrolled in the study, then administered educational and occupational questionnaires 16 years later.
Boys with ADHD completed 2.5 fewer years of school than controls (P=.001). Although rates of employment for the 2 groups were the same at 90%, those with ADHD had a significantly poorer occupational ranking than controls using the Hollingshead and Redlich system, which rates occupations on 7-point scale, with 1 representing top-ranked occupations. Individuals with ADHD scored 4.4 points compared with 3.5 points for the control group (P<.001). However, by the end of the study, more individuals with ADHD owned and operated their own businesses compared with controls (18% vs 5%; P<.01).1
Fewer degrees but comparable employment rates
A similar prospective cohort study evaluated educational and occupational outcomes among 104 boys with ADHD and 106 controls. Investigators recruited boys 5 to 11 years of age from a psychiatric research clinic and followed them for a mean of 17 years using educational and occupational questionnaires.
Boys with ADHD completed 2 fewer years of school than controls (P=.0001), and more boys in the ADHD group failed to complete high school (25% vs 1%; P value not supplied). Fewer individuals with ADHD than controls obtained a bachelor’s degree (15% vs 50%; P<.001), and fewer enrolled in graduate school (3% vs 16%; P value not given). Employment was comparable in the 2 groups, however (92% vs 93%, P=.07).2
Less success in school and at work
Another prospective case-control study also found that people with ADHD achieved less educational and occupational success than controls. The study compared 224 subjects between 18 and 55 years of age with ADHD from a psychiatric referral clinic with 146 controls matched for age and intelligence quotient (IQ). Investigators correlated predicted educational achievement based on IQ in the controls with that observed in subjects with ADHD.
Five years later, subjects with ADHD didn’t perform as well as predicted. Fewer earned college degrees (29% vs 52%) or graduate degrees (20% vs 33%), and more earned no college or graduate school degrees (50% vs 16%) (P<.001 for comparison of observed compared with expected means using Wilcoxon matched pairs test). Similarly, fewer subjects with ADHD attained a level of 6 on the Hollingshead Socioeconomic Status Scale than controls (58% vs 80%; P<.001).3
Recommendations
We found no statements from national organizations about the long-term educational prognosis for children and adolescents with ADHD. However, the authors of the Multimodal Treatment Study of Children with ADHD have expressed the opinion that prognosis depends on initial presentation (including severity of symptoms and comorbid conduct disorders), intellect, social advantage, and response to treatment.4
1. Mannuzza S, Klein RG, Bessler A, et al. Adult outcome of hyperactive boys: educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry. 1993;50:565-576.
2. Mannuzza S, Klein RG, Bessler A, et al. Educational and occupational outcome of hyperactive boys grown up. J Am Acad Child Adolesc Psychiatry. 1997;36:1222-1227.
3. Biederman J, Petty CR, Fried R, et al. Educational and occupational underattainment in adults with attention-deficit/hyperactivity disorder: a controlled study. J Clin Psychiatry. 2008;69:1217-1222.
4. Molina BS, Hinshaw SP, Swanson JM, et al. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry. 2009;48:484-500.
1. Mannuzza S, Klein RG, Bessler A, et al. Adult outcome of hyperactive boys: educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry. 1993;50:565-576.
2. Mannuzza S, Klein RG, Bessler A, et al. Educational and occupational outcome of hyperactive boys grown up. J Am Acad Child Adolesc Psychiatry. 1997;36:1222-1227.
3. Biederman J, Petty CR, Fried R, et al. Educational and occupational underattainment in adults with attention-deficit/hyperactivity disorder: a controlled study. J Clin Psychiatry. 2008;69:1217-1222.
4. Molina BS, Hinshaw SP, Swanson JM, et al. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry. 2009;48:484-500.
Evidence-based answers from the Family Physicians Inquiries Network
How effective—and safe—are systemic steroids for acute low back pain?
SHORT COURSES OF SYSTEMIC STEROIDS ARE LIKELY SAFE, but they are ineffective. A single dose of intramuscular (IM) or intravenous (IV) methylprednisolone doesn’t improve long-term pain scores in patients with low back pain and sciatica and produces conflicting effects on function. Oral prednisone (9-day taper) doesn’t improve pain or function in patients with back pain and sciatica. A single IM dose of methylprednisolone doesn’t improve pain scores or function in patients with back pain without sciatica (strength of recommendation: B, randomized controlled trials [RCTs]).
No trials of corticosteroids for back pain reported an increase in adverse outcomes, but studies were small, and only short-term (1 month) follow-up data are available.
Evidence summary
A double-blind RCT of 82 patients who reported to an emergency department with acute low back pain and sciatica compared the efficacy of a single IM dose of 160 mg methylprednisolone with placebo.1 Sciatica was confirmed with a positive straight leg test. All patients were given an instruction sheet and a small supply of naproxen and oxycodone with acetaminophen. The primary outcome was change in pain score, rated on a 0-to-10 visual analog scale (VAS).
Pain scores dropped in both groups over time. The magnitude of the change was not significantly greater in the steroid group (at 1 week: mean difference=1.1; 95% confidence interval [CI], –0.5 to 2.8; at 1 month: mean difference=1.3; 95% CI, –0.5 to 2.7).
Among secondary outcomes at 1 month, 19% of the methylprednisolone group reported continued functional disability compared with 49% of the placebo group (absolute difference=30%; 95% CI, 9-49; P=.007). Analgesic use in the previous 24 hours was similar for both groups (22% with steroid injection vs 43% with placebo; P=.06). There were no reports of gastrointestinal bleeding, osteonecrosis, infection, or serious hyperglycemia.
The same applies to back pain without sciatica
Another double-blind RCT of 87 patients evaluated IM methylprednisolone for acute low back pain of less than 1 week duration without sciatica.2 Patients received a single IM dose of 160 mg methylprednisolone or placebo. Both groups were given an instruction sheet and a small supply of naproxen and oxycodone with acetaminophen. The primary outcome was change in pain score on a 0-to-10 VAS.
Pain scores dropped in both groups over time, but the reduction wasn’t significantly larger in the steroid group (at 1 week: mean difference=0.6; 95% CI, –0.9 to 2.2; at 1 month: mean difference=0.6; 95% CI, –1.0 to 2.2). At 1 month, neither functional status nor “medication use in the preceding 24 hours” differed between the 2 groups.
The most common adverse effects were upper gastrointestinal complaints, drowsiness, and weakness. Adverse effect rates were comparable for the 2 groups and believed to be caused by the naproxen and oxycodone all patients received.
Relief of sciatica with IV steroids is short-lived
A double-blind RCT evaluated the efficacy of a single IV dose of 500 mg methylprednisolone or placebo for 65 patients with leg sciatica (with or without back pain) associated with imaging-confirmed lumbar disk disease.3 The primary outcome was reduction in sciatic leg pain during the first 3 days after injection as measured on a 100-mm VAS. All patients received standard pain medication and physical therapy.
At day 1, 48% of the methylprednisolone group and 28% of the placebo group showed a decrease on the VAS for sciatic pain of 20 mm or more (P=.04; number needed to treat=5). Pain measurements at 2, 3, 10, and 30 days found no significant difference between the groups, however. Nor did the groups differ significantly in functional status or medication use. The study didn’t assess adverse events.
Oral prednisone relieves back pain with sciatica no better than placebo
A double-blind RCT compared an oral prednisone taper (60 mg, 40 mg, and 20 mg each for 3 days) with placebo for treating 27 patients with acute low back pain and sciatica.4 All patients received nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotics for pain control, directions to engage in activity as tolerated, and a referral for physical therapy. Outcomes were evaluated weekly for 1 month, then monthly for 5 months.
Pain scores, functional ability, and medication use didn’t differ significantly between the 2 groups. Steroid injections were later given to 15% of the oral steroid group and 43% of the control group, but the difference in outcomes wasn’t statistically significant. Investigators didn’t assess adverse events.
Recommendations
The joint guidelines of the American College of Physicians and the American Pain Society recommend acetaminophen and NSAIDs as first-line treatments for back pain and back pain with sciatica.5 The guidelines advise against using systemic corticosteroids because “they have not been shown to be more effective than placebo.”
1. Friedman BW, Esses D, Solorzano C, et al. A randomized placebo-controlled trial of single-dose IM corticosteroid for radicular low back pain. Spine. 2008;33:E624-E629.
2. Friedman BW, Holden L, Esses D, et al. Parenteral corticosteroids for emergency department patients with nonradicular low back pain. J Emerg Med. 2006;31:365-370.
3. Finckh A, Zufferey P, Schurch MA, et al. Short-term efficacy of intravenous pulse glucocorticoids in acute discogenic sciatica: a randomized controlled trial. Spine. 2006;31:377-381.
4. Holve RL, Barkan H. Oral steroids in initial treatment of acute sciatica. J Am Board Fam Med. 2008;21:469-474.
5. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147:478-491.
SHORT COURSES OF SYSTEMIC STEROIDS ARE LIKELY SAFE, but they are ineffective. A single dose of intramuscular (IM) or intravenous (IV) methylprednisolone doesn’t improve long-term pain scores in patients with low back pain and sciatica and produces conflicting effects on function. Oral prednisone (9-day taper) doesn’t improve pain or function in patients with back pain and sciatica. A single IM dose of methylprednisolone doesn’t improve pain scores or function in patients with back pain without sciatica (strength of recommendation: B, randomized controlled trials [RCTs]).
No trials of corticosteroids for back pain reported an increase in adverse outcomes, but studies were small, and only short-term (1 month) follow-up data are available.
Evidence summary
A double-blind RCT of 82 patients who reported to an emergency department with acute low back pain and sciatica compared the efficacy of a single IM dose of 160 mg methylprednisolone with placebo.1 Sciatica was confirmed with a positive straight leg test. All patients were given an instruction sheet and a small supply of naproxen and oxycodone with acetaminophen. The primary outcome was change in pain score, rated on a 0-to-10 visual analog scale (VAS).
Pain scores dropped in both groups over time. The magnitude of the change was not significantly greater in the steroid group (at 1 week: mean difference=1.1; 95% confidence interval [CI], –0.5 to 2.8; at 1 month: mean difference=1.3; 95% CI, –0.5 to 2.7).
Among secondary outcomes at 1 month, 19% of the methylprednisolone group reported continued functional disability compared with 49% of the placebo group (absolute difference=30%; 95% CI, 9-49; P=.007). Analgesic use in the previous 24 hours was similar for both groups (22% with steroid injection vs 43% with placebo; P=.06). There were no reports of gastrointestinal bleeding, osteonecrosis, infection, or serious hyperglycemia.
The same applies to back pain without sciatica
Another double-blind RCT of 87 patients evaluated IM methylprednisolone for acute low back pain of less than 1 week duration without sciatica.2 Patients received a single IM dose of 160 mg methylprednisolone or placebo. Both groups were given an instruction sheet and a small supply of naproxen and oxycodone with acetaminophen. The primary outcome was change in pain score on a 0-to-10 VAS.
Pain scores dropped in both groups over time, but the reduction wasn’t significantly larger in the steroid group (at 1 week: mean difference=0.6; 95% CI, –0.9 to 2.2; at 1 month: mean difference=0.6; 95% CI, –1.0 to 2.2). At 1 month, neither functional status nor “medication use in the preceding 24 hours” differed between the 2 groups.
The most common adverse effects were upper gastrointestinal complaints, drowsiness, and weakness. Adverse effect rates were comparable for the 2 groups and believed to be caused by the naproxen and oxycodone all patients received.
Relief of sciatica with IV steroids is short-lived
A double-blind RCT evaluated the efficacy of a single IV dose of 500 mg methylprednisolone or placebo for 65 patients with leg sciatica (with or without back pain) associated with imaging-confirmed lumbar disk disease.3 The primary outcome was reduction in sciatic leg pain during the first 3 days after injection as measured on a 100-mm VAS. All patients received standard pain medication and physical therapy.
At day 1, 48% of the methylprednisolone group and 28% of the placebo group showed a decrease on the VAS for sciatic pain of 20 mm or more (P=.04; number needed to treat=5). Pain measurements at 2, 3, 10, and 30 days found no significant difference between the groups, however. Nor did the groups differ significantly in functional status or medication use. The study didn’t assess adverse events.
Oral prednisone relieves back pain with sciatica no better than placebo
A double-blind RCT compared an oral prednisone taper (60 mg, 40 mg, and 20 mg each for 3 days) with placebo for treating 27 patients with acute low back pain and sciatica.4 All patients received nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotics for pain control, directions to engage in activity as tolerated, and a referral for physical therapy. Outcomes were evaluated weekly for 1 month, then monthly for 5 months.
Pain scores, functional ability, and medication use didn’t differ significantly between the 2 groups. Steroid injections were later given to 15% of the oral steroid group and 43% of the control group, but the difference in outcomes wasn’t statistically significant. Investigators didn’t assess adverse events.
Recommendations
The joint guidelines of the American College of Physicians and the American Pain Society recommend acetaminophen and NSAIDs as first-line treatments for back pain and back pain with sciatica.5 The guidelines advise against using systemic corticosteroids because “they have not been shown to be more effective than placebo.”
SHORT COURSES OF SYSTEMIC STEROIDS ARE LIKELY SAFE, but they are ineffective. A single dose of intramuscular (IM) or intravenous (IV) methylprednisolone doesn’t improve long-term pain scores in patients with low back pain and sciatica and produces conflicting effects on function. Oral prednisone (9-day taper) doesn’t improve pain or function in patients with back pain and sciatica. A single IM dose of methylprednisolone doesn’t improve pain scores or function in patients with back pain without sciatica (strength of recommendation: B, randomized controlled trials [RCTs]).
No trials of corticosteroids for back pain reported an increase in adverse outcomes, but studies were small, and only short-term (1 month) follow-up data are available.
Evidence summary
A double-blind RCT of 82 patients who reported to an emergency department with acute low back pain and sciatica compared the efficacy of a single IM dose of 160 mg methylprednisolone with placebo.1 Sciatica was confirmed with a positive straight leg test. All patients were given an instruction sheet and a small supply of naproxen and oxycodone with acetaminophen. The primary outcome was change in pain score, rated on a 0-to-10 visual analog scale (VAS).
Pain scores dropped in both groups over time. The magnitude of the change was not significantly greater in the steroid group (at 1 week: mean difference=1.1; 95% confidence interval [CI], –0.5 to 2.8; at 1 month: mean difference=1.3; 95% CI, –0.5 to 2.7).
Among secondary outcomes at 1 month, 19% of the methylprednisolone group reported continued functional disability compared with 49% of the placebo group (absolute difference=30%; 95% CI, 9-49; P=.007). Analgesic use in the previous 24 hours was similar for both groups (22% with steroid injection vs 43% with placebo; P=.06). There were no reports of gastrointestinal bleeding, osteonecrosis, infection, or serious hyperglycemia.
The same applies to back pain without sciatica
Another double-blind RCT of 87 patients evaluated IM methylprednisolone for acute low back pain of less than 1 week duration without sciatica.2 Patients received a single IM dose of 160 mg methylprednisolone or placebo. Both groups were given an instruction sheet and a small supply of naproxen and oxycodone with acetaminophen. The primary outcome was change in pain score on a 0-to-10 VAS.
Pain scores dropped in both groups over time, but the reduction wasn’t significantly larger in the steroid group (at 1 week: mean difference=0.6; 95% CI, –0.9 to 2.2; at 1 month: mean difference=0.6; 95% CI, –1.0 to 2.2). At 1 month, neither functional status nor “medication use in the preceding 24 hours” differed between the 2 groups.
The most common adverse effects were upper gastrointestinal complaints, drowsiness, and weakness. Adverse effect rates were comparable for the 2 groups and believed to be caused by the naproxen and oxycodone all patients received.
Relief of sciatica with IV steroids is short-lived
A double-blind RCT evaluated the efficacy of a single IV dose of 500 mg methylprednisolone or placebo for 65 patients with leg sciatica (with or without back pain) associated with imaging-confirmed lumbar disk disease.3 The primary outcome was reduction in sciatic leg pain during the first 3 days after injection as measured on a 100-mm VAS. All patients received standard pain medication and physical therapy.
At day 1, 48% of the methylprednisolone group and 28% of the placebo group showed a decrease on the VAS for sciatic pain of 20 mm or more (P=.04; number needed to treat=5). Pain measurements at 2, 3, 10, and 30 days found no significant difference between the groups, however. Nor did the groups differ significantly in functional status or medication use. The study didn’t assess adverse events.
Oral prednisone relieves back pain with sciatica no better than placebo
A double-blind RCT compared an oral prednisone taper (60 mg, 40 mg, and 20 mg each for 3 days) with placebo for treating 27 patients with acute low back pain and sciatica.4 All patients received nonsteroidal anti-inflammatory drugs (NSAIDs) and narcotics for pain control, directions to engage in activity as tolerated, and a referral for physical therapy. Outcomes were evaluated weekly for 1 month, then monthly for 5 months.
Pain scores, functional ability, and medication use didn’t differ significantly between the 2 groups. Steroid injections were later given to 15% of the oral steroid group and 43% of the control group, but the difference in outcomes wasn’t statistically significant. Investigators didn’t assess adverse events.
Recommendations
The joint guidelines of the American College of Physicians and the American Pain Society recommend acetaminophen and NSAIDs as first-line treatments for back pain and back pain with sciatica.5 The guidelines advise against using systemic corticosteroids because “they have not been shown to be more effective than placebo.”
1. Friedman BW, Esses D, Solorzano C, et al. A randomized placebo-controlled trial of single-dose IM corticosteroid for radicular low back pain. Spine. 2008;33:E624-E629.
2. Friedman BW, Holden L, Esses D, et al. Parenteral corticosteroids for emergency department patients with nonradicular low back pain. J Emerg Med. 2006;31:365-370.
3. Finckh A, Zufferey P, Schurch MA, et al. Short-term efficacy of intravenous pulse glucocorticoids in acute discogenic sciatica: a randomized controlled trial. Spine. 2006;31:377-381.
4. Holve RL, Barkan H. Oral steroids in initial treatment of acute sciatica. J Am Board Fam Med. 2008;21:469-474.
5. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147:478-491.
1. Friedman BW, Esses D, Solorzano C, et al. A randomized placebo-controlled trial of single-dose IM corticosteroid for radicular low back pain. Spine. 2008;33:E624-E629.
2. Friedman BW, Holden L, Esses D, et al. Parenteral corticosteroids for emergency department patients with nonradicular low back pain. J Emerg Med. 2006;31:365-370.
3. Finckh A, Zufferey P, Schurch MA, et al. Short-term efficacy of intravenous pulse glucocorticoids in acute discogenic sciatica: a randomized controlled trial. Spine. 2006;31:377-381.
4. Holve RL, Barkan H. Oral steroids in initial treatment of acute sciatica. J Am Board Fam Med. 2008;21:469-474.
5. Chou R, Qaseem A, Snow V, et al. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147:478-491.
Evidence-based answers from the Family Physicians Inquiries Network
When is the best time to clamp the umbilical cord after routine vaginal delivery?
SOMETIME BETWEEN 30 SECONDS AND 2 MINUTES after delivery appears to be the best interval. In term infants, delayed clamping (waiting 1 or 2 minutes or until the cord stops pulsating) improves hemoglobin and ferritin levels, but slightly increases the risk of neonatal jaundice requiring phototherapy (strength of recommendation [SOR]: A, meta-analysis).
In preterm infants less than 37 weeks of age, cord clamping between 30 and 120 seconds after delivery reduces the need for blood transfusion (number needed to treat [NNT]=4) and frequency of intraventricular hemorrhage (NNT=8) compared with clamping in less than 20 seconds (SOR: A, meta-analyses).
Evidence summary
A 2008 Cochrane meta-analysis reviewed 11 randomized controlled trials (RCTs), enrolling more than 2900 women who had term vaginal deliveries, that compared early cord clamping (ECC) with delayed cord clamping (DCC).1 All of the trials defined ECC as clamping less than 1 minute after birth. DCC was variously defined as clamping after 1 minute, after 2 minutes, or after the cord stopped pulsating.
DCC was associated with increased newborn hemoglobin values (weighted mean difference [WMD]=2.2 g/dL; 95% confidence interval [CI], 0.3-4.1) and increased mean ferritin levels that persisted for as long as 6 months (WMD=12 mcg/L; 95% CI, 4.1-20). However, significantly fewer infants who underwent ECC required phototherapy for jaundice (relative risk [RR]=0.59; 95% CI, 0.38-0.92; NNT=45).
This meta-analysis was limited by variations in the definition of DCC, the level at which newborns were held in relation to the placenta (above, below, or level with), and the use of uterotonics. These limitations also apply to the other systematic reviews discussed here.
But is hyperbilirubinemia significant?
A 2007 meta-analysis of 15 clinical trials (8 randomized and 7 nonrandomized) with 1001 term infants in the DCC group and 911 in the ECC group found results similar to the Cochrane review.2 When compared with ECC, delayed clamping at least 2 minutes after birth was associated with significantly higher hematocrit (WMD=3.7%; 95% CI, 2-4), ferritin (WMD=18 mcg/L; 95% CI, 17-19), and stored iron (WMD=20 mg; 95% CI, 8-32), as well as decreased risk of anemia (RR=0.5; 95% CI, 0.4-0.7).
Infants in the DCC group had an increased risk of asymptomatic polycythemia (RR=3.9; 95% CI, 1.0-15). Delayed clamping was also associated with an increased rate of phototherapy for hyperbilirubinemia that didn’t reach statistical significance, although the confidence interval was wide (RR=1.78; 95% CI, 0.71-4.46).
Early clamping poses risks for preterm infants
A 2008 meta-analysis (using Cochrane methodology) identified 10 RCTs enrolling 454 infants born at less than 37 weeks’ gestation.3 ECC was defined as less than 20 seconds after delivery and DCC as greater than 30 seconds (and up to 120 seconds).
The review found ECC to be inferior to DCC. Early clamping was associated with an increased risk of transfusion for anemia (3 studies, 112 patients; RR=2.1; 95% CI, 1.2-3.3; NNT=4), increased number of blood transfusions (4 studies, 170 patients; WMD=1.2; 95% CI, 0.52-1.8), and increased rate of intraventricular hemorrhage (RR=1.9; 95% CI, 1.3-2.8; NNT=8).
Recommendations
The World Health Organization (WHO) recommends against clamping the umbilical cord any earlier than is necessary to apply traction to the placenta in the active management of the third state of labor.4 (WHO estimates this would normally take around 3 minutes.) Early clamping may be required if the baby is asphyxiated and needs immediate resuscitation.
The Society of Obstetricians and Gynecologists of Canada recommends delaying cord clamping by at least 60 seconds in premature newborns (<37 weeks’ gestation) to reduce the risk of intraventricular hemorrhage and the need for transfusion.5 For term newborns, the Society advises clinicians to weigh the increased risk of neonatal jaundice against the benefit of greater iron stores on a case-by-case basis.
1. McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev. 2008;(2):CD004074.-
2. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA. 2007;297:1241-1252.
3. Rabe H, Reynolds G, Diaz-Rossello J. A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants. Neonatology. 2008;93:138-144.
4. Abalos E. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes: RHL commentary (last revised March 2, 2009). In: The WHO Reproductive Health Library; Geneva, Switzerland: World Health Organization. Available at: http://apps.who.int/rhl/pregnancy_childbirth/childbirth/3rd_stage/cd004074_abalose_com/en/index.html. Accessed July 21, 2010.
5. Leduc D, Senikas V, Lalonde AB, et al. Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage. J Obstet Gynaecol Can. 2009;31:980-993.
SOMETIME BETWEEN 30 SECONDS AND 2 MINUTES after delivery appears to be the best interval. In term infants, delayed clamping (waiting 1 or 2 minutes or until the cord stops pulsating) improves hemoglobin and ferritin levels, but slightly increases the risk of neonatal jaundice requiring phototherapy (strength of recommendation [SOR]: A, meta-analysis).
In preterm infants less than 37 weeks of age, cord clamping between 30 and 120 seconds after delivery reduces the need for blood transfusion (number needed to treat [NNT]=4) and frequency of intraventricular hemorrhage (NNT=8) compared with clamping in less than 20 seconds (SOR: A, meta-analyses).
Evidence summary
A 2008 Cochrane meta-analysis reviewed 11 randomized controlled trials (RCTs), enrolling more than 2900 women who had term vaginal deliveries, that compared early cord clamping (ECC) with delayed cord clamping (DCC).1 All of the trials defined ECC as clamping less than 1 minute after birth. DCC was variously defined as clamping after 1 minute, after 2 minutes, or after the cord stopped pulsating.
DCC was associated with increased newborn hemoglobin values (weighted mean difference [WMD]=2.2 g/dL; 95% confidence interval [CI], 0.3-4.1) and increased mean ferritin levels that persisted for as long as 6 months (WMD=12 mcg/L; 95% CI, 4.1-20). However, significantly fewer infants who underwent ECC required phototherapy for jaundice (relative risk [RR]=0.59; 95% CI, 0.38-0.92; NNT=45).
This meta-analysis was limited by variations in the definition of DCC, the level at which newborns were held in relation to the placenta (above, below, or level with), and the use of uterotonics. These limitations also apply to the other systematic reviews discussed here.
But is hyperbilirubinemia significant?
A 2007 meta-analysis of 15 clinical trials (8 randomized and 7 nonrandomized) with 1001 term infants in the DCC group and 911 in the ECC group found results similar to the Cochrane review.2 When compared with ECC, delayed clamping at least 2 minutes after birth was associated with significantly higher hematocrit (WMD=3.7%; 95% CI, 2-4), ferritin (WMD=18 mcg/L; 95% CI, 17-19), and stored iron (WMD=20 mg; 95% CI, 8-32), as well as decreased risk of anemia (RR=0.5; 95% CI, 0.4-0.7).
Infants in the DCC group had an increased risk of asymptomatic polycythemia (RR=3.9; 95% CI, 1.0-15). Delayed clamping was also associated with an increased rate of phototherapy for hyperbilirubinemia that didn’t reach statistical significance, although the confidence interval was wide (RR=1.78; 95% CI, 0.71-4.46).
Early clamping poses risks for preterm infants
A 2008 meta-analysis (using Cochrane methodology) identified 10 RCTs enrolling 454 infants born at less than 37 weeks’ gestation.3 ECC was defined as less than 20 seconds after delivery and DCC as greater than 30 seconds (and up to 120 seconds).
The review found ECC to be inferior to DCC. Early clamping was associated with an increased risk of transfusion for anemia (3 studies, 112 patients; RR=2.1; 95% CI, 1.2-3.3; NNT=4), increased number of blood transfusions (4 studies, 170 patients; WMD=1.2; 95% CI, 0.52-1.8), and increased rate of intraventricular hemorrhage (RR=1.9; 95% CI, 1.3-2.8; NNT=8).
Recommendations
The World Health Organization (WHO) recommends against clamping the umbilical cord any earlier than is necessary to apply traction to the placenta in the active management of the third state of labor.4 (WHO estimates this would normally take around 3 minutes.) Early clamping may be required if the baby is asphyxiated and needs immediate resuscitation.
The Society of Obstetricians and Gynecologists of Canada recommends delaying cord clamping by at least 60 seconds in premature newborns (<37 weeks’ gestation) to reduce the risk of intraventricular hemorrhage and the need for transfusion.5 For term newborns, the Society advises clinicians to weigh the increased risk of neonatal jaundice against the benefit of greater iron stores on a case-by-case basis.
SOMETIME BETWEEN 30 SECONDS AND 2 MINUTES after delivery appears to be the best interval. In term infants, delayed clamping (waiting 1 or 2 minutes or until the cord stops pulsating) improves hemoglobin and ferritin levels, but slightly increases the risk of neonatal jaundice requiring phototherapy (strength of recommendation [SOR]: A, meta-analysis).
In preterm infants less than 37 weeks of age, cord clamping between 30 and 120 seconds after delivery reduces the need for blood transfusion (number needed to treat [NNT]=4) and frequency of intraventricular hemorrhage (NNT=8) compared with clamping in less than 20 seconds (SOR: A, meta-analyses).
Evidence summary
A 2008 Cochrane meta-analysis reviewed 11 randomized controlled trials (RCTs), enrolling more than 2900 women who had term vaginal deliveries, that compared early cord clamping (ECC) with delayed cord clamping (DCC).1 All of the trials defined ECC as clamping less than 1 minute after birth. DCC was variously defined as clamping after 1 minute, after 2 minutes, or after the cord stopped pulsating.
DCC was associated with increased newborn hemoglobin values (weighted mean difference [WMD]=2.2 g/dL; 95% confidence interval [CI], 0.3-4.1) and increased mean ferritin levels that persisted for as long as 6 months (WMD=12 mcg/L; 95% CI, 4.1-20). However, significantly fewer infants who underwent ECC required phototherapy for jaundice (relative risk [RR]=0.59; 95% CI, 0.38-0.92; NNT=45).
This meta-analysis was limited by variations in the definition of DCC, the level at which newborns were held in relation to the placenta (above, below, or level with), and the use of uterotonics. These limitations also apply to the other systematic reviews discussed here.
But is hyperbilirubinemia significant?
A 2007 meta-analysis of 15 clinical trials (8 randomized and 7 nonrandomized) with 1001 term infants in the DCC group and 911 in the ECC group found results similar to the Cochrane review.2 When compared with ECC, delayed clamping at least 2 minutes after birth was associated with significantly higher hematocrit (WMD=3.7%; 95% CI, 2-4), ferritin (WMD=18 mcg/L; 95% CI, 17-19), and stored iron (WMD=20 mg; 95% CI, 8-32), as well as decreased risk of anemia (RR=0.5; 95% CI, 0.4-0.7).
Infants in the DCC group had an increased risk of asymptomatic polycythemia (RR=3.9; 95% CI, 1.0-15). Delayed clamping was also associated with an increased rate of phototherapy for hyperbilirubinemia that didn’t reach statistical significance, although the confidence interval was wide (RR=1.78; 95% CI, 0.71-4.46).
Early clamping poses risks for preterm infants
A 2008 meta-analysis (using Cochrane methodology) identified 10 RCTs enrolling 454 infants born at less than 37 weeks’ gestation.3 ECC was defined as less than 20 seconds after delivery and DCC as greater than 30 seconds (and up to 120 seconds).
The review found ECC to be inferior to DCC. Early clamping was associated with an increased risk of transfusion for anemia (3 studies, 112 patients; RR=2.1; 95% CI, 1.2-3.3; NNT=4), increased number of blood transfusions (4 studies, 170 patients; WMD=1.2; 95% CI, 0.52-1.8), and increased rate of intraventricular hemorrhage (RR=1.9; 95% CI, 1.3-2.8; NNT=8).
Recommendations
The World Health Organization (WHO) recommends against clamping the umbilical cord any earlier than is necessary to apply traction to the placenta in the active management of the third state of labor.4 (WHO estimates this would normally take around 3 minutes.) Early clamping may be required if the baby is asphyxiated and needs immediate resuscitation.
The Society of Obstetricians and Gynecologists of Canada recommends delaying cord clamping by at least 60 seconds in premature newborns (<37 weeks’ gestation) to reduce the risk of intraventricular hemorrhage and the need for transfusion.5 For term newborns, the Society advises clinicians to weigh the increased risk of neonatal jaundice against the benefit of greater iron stores on a case-by-case basis.
1. McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev. 2008;(2):CD004074.-
2. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA. 2007;297:1241-1252.
3. Rabe H, Reynolds G, Diaz-Rossello J. A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants. Neonatology. 2008;93:138-144.
4. Abalos E. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes: RHL commentary (last revised March 2, 2009). In: The WHO Reproductive Health Library; Geneva, Switzerland: World Health Organization. Available at: http://apps.who.int/rhl/pregnancy_childbirth/childbirth/3rd_stage/cd004074_abalose_com/en/index.html. Accessed July 21, 2010.
5. Leduc D, Senikas V, Lalonde AB, et al. Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage. J Obstet Gynaecol Can. 2009;31:980-993.
1. McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev. 2008;(2):CD004074.-
2. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA. 2007;297:1241-1252.
3. Rabe H, Reynolds G, Diaz-Rossello J. A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants. Neonatology. 2008;93:138-144.
4. Abalos E. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes: RHL commentary (last revised March 2, 2009). In: The WHO Reproductive Health Library; Geneva, Switzerland: World Health Organization. Available at: http://apps.who.int/rhl/pregnancy_childbirth/childbirth/3rd_stage/cd004074_abalose_com/en/index.html. Accessed July 21, 2010.
5. Leduc D, Senikas V, Lalonde AB, et al. Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage. J Obstet Gynaecol Can. 2009;31:980-993.
Evidence-based answers from the Family Physicians Inquiries Network
Which treatments provide the most relief for pharyngitis pain?
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs), acetaminophen, antibiotics, and oral and intramuscular steroids are effective (strength of recommendation [SOR]: A, meta-analysis).
Ibuprofen relieves pain more effectively than acetaminophen (SOR: A, meta-analysis). Antibiotics reduce pain in confirmed bacterial infections (SOR: A, multiple randomized controlled trials [RCTs]). Steroids are superior to placebo (SOR: A, meta-analysis).
Traditional demulcents, agents that help form a film over mucous membranes, provide less than 30 minutes of pain relief (SOR: B, small RCT); demulcents that contain benzocaine or lidocaine are longer acting (SOR: B, small RCT).
The efficacy of herbal remedies can’t be determined because of lack of high-quality studies (SOR: A, meta-analysis). Zinc doesn’t reduce pharyngitis symptoms (SOR: A, meta-analysis).
Evidence summary
A meta-analysis of 54 RCTs that investigated pain control, 5 of which focused on pharyngitis, showed that both ibuprofen and acetaminophen are more effective than placebo.1 In the 3 adult RCTs (N=346) and 2 pediatric RCTs (N=347) that studied pharyngitis specifically, 400 mg ibuprofen 3 times a day (10 mg/kg in children) provided more pain relief than 1000 mg acetaminophen 3 times a day (15 mg/kg in children).1
One of the RCTs, a double-blind, single-dose, single-center study of pharyngitis, found that 400 mg ibuprofen reduced pain by 80% at 3 hours compared with a 50% decrease for 1000 mg acetaminophen (P<.01).2 At 6 hours, ibuprofen still produced 70% relief compared with 20% for acetaminophen (P<.01). The meta-analysis demonstrated no significant difference in side effects between the 2 drugs.1
Steroids help, but concomitant antibiotics muddy the data
A meta-analysis of 8 RCTs enrolling 743 patients (369 children and 374 adults) found that oral and intramuscular steroids reduce duration and intensity of pain in moderate to severe pharyngitis and exudative pharyngitis.3 Four of the studies showed that corticosteroids completely resolve pain at 24 hours compared with placebo (number needed to treat [NNT]=3.7; 95% confidence interval [CI], 2.8-5.9), and 3 studies demonstrated pain relief at 48 hours (NNT=3.3; 95% CI, 2.4-5.6).
Although time to pain resolution varied among the studies, the research demonstrated a decrease in mean onset of pain relief by 6 hours compared with placebo (95% CI, 3.4-9.3; P<.001).3 All of the studies in the meta-analysis were limited by the fact that steroids were given in combination with antibiotics.
Demulcents have short-lived effect with a boost from anesthetics
A multicenter, prospective, randomized, double-blinded, placebo-controlled study (N=60) showed that demulcents provide short-term pain relief. On combined self-reported pain scales at 5, 10, 15, and 30 minutes, herbal tea demulcents were more effective than placebo (mean improvement in overall pain score=66.7 ± 39.2 on a 150-point scale, compared with 48.7 ± 32.8; P=.031). No difference was seen after 30 minutes.4
Demulcents with added anesthetics provide superior pain relief compared to placebo, as measured on a visual analog scale. In a single-center, randomized, double-blinded, placebo-controlled phase III study (N=240), patients who reported meaningful pain relief with lidocaine lozenges compared with placebo showed benefit from both single doses (38.3% lozenges vs 11.7% placebo; NNT=3.8) and multiple doses (73.3% lozenges vs 34.2% placebo; NNT=2.5). Additionally, pain relief lasted for >2 hours per lozenge. They also experienced more rapid onset of relief (24 minutes on average compared with 41 minutes).5
Antibiotics work better in patients with strep
A Cochrane review comparing antibiotics with placebo for sore throat showed an NNT of 5.8 (relative risk [RR]=0.68; 95% CI, 0.59-0.79) for pain resolution by Day 3 and an NNT of 21 (RR=0.49; 95% CI, 0.32-0.76) for pain resolution by Day 7. Antibiotics reduced pain more effectively in patients who tested positive for Streptococcus (RR=0.58; 95% CI, 0.48-0.71) than patients who tested negative (RR=0.78; 95% CI 0.63-0.97).6
Don’t bother with herbals or zinc
A Cochrane review of 7 RCTs of Chinese herbal remedies for sore throat pain found poor-quality methodology and thus, couldn’t recommend their use.7
A Cochrane review of zinc supplementation (13 therapeutic trials [N=966] and 2 preventive trials [N=394]) showed no significant improvement in pharyngitis symptoms compared with placebo, although zinc decreases the duration of the common cold, if taken within the first 24 hours of cold onset (standardized mean difference, -0.97; 95% CI, -1.56 to -0.38; P=.001).8 More patients in the intervention group experienced side effects (bad taste and nausea).
Recommendations
A primary care review article in the New England Journal of Medicine recommended acetaminophen as the drug of choice, while noting that ibuprofen has been shown in some studies to be more effective.9 The authors also recommended anesthetic gargles or lozenges. Antibiotics should be used in medical management only to prevent complications from Streptococcus-antigen-confirmed pharyngitis, they say.
Treatments recommended by the Institute for Clinical Systems Improvement include acetaminophen or ibuprofen, throat lozenges or hard candy, gargling with salt water (¼ tsp salt per 8 oz water), eating soft foods and frozen desserts, drinking cool or warm liquids, and antibiotics for bacterial infections.10
1. Pierce CA. Efficacy and safety of ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review. Ann Pharmacother. 2010;44:489-506.
2. Schachtel BP, Fillingim JM, Thoden WR, et al. Sore throat pain in the evaluation of mild analgesics. Clin Pharmacol Ther. 1988;44:704-711.
3. Hayward G, Thompson M, Heneghan C, et al. Corticosteroids for pain relief in sore throat: systemic review and metaanalysis. BMJ. 2009;339:b2976.-
4. Brinckmann J, Sigwart H, van Houten L Taylor. Safety and efficacy of a traditional herbal medicine (Throat Coat) in symptomatic temporary relief of pain in patients with acute pharyngitis: a multicenter, prospective, randomized, double-blinded, placebo-controlled study. J Altern Complement Med. 2003;9:285-298.
5. Wonnemann M, Helm I, Strauss-Grabo M, et al. Lidocaine 8 mg sore throat lozenges in the treatment of acute pharyngitis. A new therapeutic option investigated in comparison to placebo treatment. Arznelmittelforschung. 2007;57:689-697.
6. Spinks A, Glasziou PP, Del Mar C. Antibiotics for sore throat. Cochrane Database Syst Rev. 2010;(2):CD000023.-
7. Shi Y, Gu R, Liu C, et al. Chinese medicinal herbs for sore throat. Cochrane Database Syst Rev. 2010;(3):CD004877.-
8. Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev. 2011;(2):CD001364.-
9. Bisno AL. Acute pharyngitis. N Engl J Med. 2001;344:201-211.
10. Institute for Clinical Systems Improvement. Diagnosis and treatment of respiratory illness in children and adults. Available at: www.icsi.org/guidelines_and_more/gl_os_prot/respiratory/respiratory_illness_in_children_and_adults__guideline_/respiratory_illness_in_children_and_adults__guideline__13110.html. Accessed February 10, 2011.
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs), acetaminophen, antibiotics, and oral and intramuscular steroids are effective (strength of recommendation [SOR]: A, meta-analysis).
Ibuprofen relieves pain more effectively than acetaminophen (SOR: A, meta-analysis). Antibiotics reduce pain in confirmed bacterial infections (SOR: A, multiple randomized controlled trials [RCTs]). Steroids are superior to placebo (SOR: A, meta-analysis).
Traditional demulcents, agents that help form a film over mucous membranes, provide less than 30 minutes of pain relief (SOR: B, small RCT); demulcents that contain benzocaine or lidocaine are longer acting (SOR: B, small RCT).
The efficacy of herbal remedies can’t be determined because of lack of high-quality studies (SOR: A, meta-analysis). Zinc doesn’t reduce pharyngitis symptoms (SOR: A, meta-analysis).
Evidence summary
A meta-analysis of 54 RCTs that investigated pain control, 5 of which focused on pharyngitis, showed that both ibuprofen and acetaminophen are more effective than placebo.1 In the 3 adult RCTs (N=346) and 2 pediatric RCTs (N=347) that studied pharyngitis specifically, 400 mg ibuprofen 3 times a day (10 mg/kg in children) provided more pain relief than 1000 mg acetaminophen 3 times a day (15 mg/kg in children).1
One of the RCTs, a double-blind, single-dose, single-center study of pharyngitis, found that 400 mg ibuprofen reduced pain by 80% at 3 hours compared with a 50% decrease for 1000 mg acetaminophen (P<.01).2 At 6 hours, ibuprofen still produced 70% relief compared with 20% for acetaminophen (P<.01). The meta-analysis demonstrated no significant difference in side effects between the 2 drugs.1
Steroids help, but concomitant antibiotics muddy the data
A meta-analysis of 8 RCTs enrolling 743 patients (369 children and 374 adults) found that oral and intramuscular steroids reduce duration and intensity of pain in moderate to severe pharyngitis and exudative pharyngitis.3 Four of the studies showed that corticosteroids completely resolve pain at 24 hours compared with placebo (number needed to treat [NNT]=3.7; 95% confidence interval [CI], 2.8-5.9), and 3 studies demonstrated pain relief at 48 hours (NNT=3.3; 95% CI, 2.4-5.6).
Although time to pain resolution varied among the studies, the research demonstrated a decrease in mean onset of pain relief by 6 hours compared with placebo (95% CI, 3.4-9.3; P<.001).3 All of the studies in the meta-analysis were limited by the fact that steroids were given in combination with antibiotics.
Demulcents have short-lived effect with a boost from anesthetics
A multicenter, prospective, randomized, double-blinded, placebo-controlled study (N=60) showed that demulcents provide short-term pain relief. On combined self-reported pain scales at 5, 10, 15, and 30 minutes, herbal tea demulcents were more effective than placebo (mean improvement in overall pain score=66.7 ± 39.2 on a 150-point scale, compared with 48.7 ± 32.8; P=.031). No difference was seen after 30 minutes.4
Demulcents with added anesthetics provide superior pain relief compared to placebo, as measured on a visual analog scale. In a single-center, randomized, double-blinded, placebo-controlled phase III study (N=240), patients who reported meaningful pain relief with lidocaine lozenges compared with placebo showed benefit from both single doses (38.3% lozenges vs 11.7% placebo; NNT=3.8) and multiple doses (73.3% lozenges vs 34.2% placebo; NNT=2.5). Additionally, pain relief lasted for >2 hours per lozenge. They also experienced more rapid onset of relief (24 minutes on average compared with 41 minutes).5
Antibiotics work better in patients with strep
A Cochrane review comparing antibiotics with placebo for sore throat showed an NNT of 5.8 (relative risk [RR]=0.68; 95% CI, 0.59-0.79) for pain resolution by Day 3 and an NNT of 21 (RR=0.49; 95% CI, 0.32-0.76) for pain resolution by Day 7. Antibiotics reduced pain more effectively in patients who tested positive for Streptococcus (RR=0.58; 95% CI, 0.48-0.71) than patients who tested negative (RR=0.78; 95% CI 0.63-0.97).6
Don’t bother with herbals or zinc
A Cochrane review of 7 RCTs of Chinese herbal remedies for sore throat pain found poor-quality methodology and thus, couldn’t recommend their use.7
A Cochrane review of zinc supplementation (13 therapeutic trials [N=966] and 2 preventive trials [N=394]) showed no significant improvement in pharyngitis symptoms compared with placebo, although zinc decreases the duration of the common cold, if taken within the first 24 hours of cold onset (standardized mean difference, -0.97; 95% CI, -1.56 to -0.38; P=.001).8 More patients in the intervention group experienced side effects (bad taste and nausea).
Recommendations
A primary care review article in the New England Journal of Medicine recommended acetaminophen as the drug of choice, while noting that ibuprofen has been shown in some studies to be more effective.9 The authors also recommended anesthetic gargles or lozenges. Antibiotics should be used in medical management only to prevent complications from Streptococcus-antigen-confirmed pharyngitis, they say.
Treatments recommended by the Institute for Clinical Systems Improvement include acetaminophen or ibuprofen, throat lozenges or hard candy, gargling with salt water (¼ tsp salt per 8 oz water), eating soft foods and frozen desserts, drinking cool or warm liquids, and antibiotics for bacterial infections.10
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs), acetaminophen, antibiotics, and oral and intramuscular steroids are effective (strength of recommendation [SOR]: A, meta-analysis).
Ibuprofen relieves pain more effectively than acetaminophen (SOR: A, meta-analysis). Antibiotics reduce pain in confirmed bacterial infections (SOR: A, multiple randomized controlled trials [RCTs]). Steroids are superior to placebo (SOR: A, meta-analysis).
Traditional demulcents, agents that help form a film over mucous membranes, provide less than 30 minutes of pain relief (SOR: B, small RCT); demulcents that contain benzocaine or lidocaine are longer acting (SOR: B, small RCT).
The efficacy of herbal remedies can’t be determined because of lack of high-quality studies (SOR: A, meta-analysis). Zinc doesn’t reduce pharyngitis symptoms (SOR: A, meta-analysis).
Evidence summary
A meta-analysis of 54 RCTs that investigated pain control, 5 of which focused on pharyngitis, showed that both ibuprofen and acetaminophen are more effective than placebo.1 In the 3 adult RCTs (N=346) and 2 pediatric RCTs (N=347) that studied pharyngitis specifically, 400 mg ibuprofen 3 times a day (10 mg/kg in children) provided more pain relief than 1000 mg acetaminophen 3 times a day (15 mg/kg in children).1
One of the RCTs, a double-blind, single-dose, single-center study of pharyngitis, found that 400 mg ibuprofen reduced pain by 80% at 3 hours compared with a 50% decrease for 1000 mg acetaminophen (P<.01).2 At 6 hours, ibuprofen still produced 70% relief compared with 20% for acetaminophen (P<.01). The meta-analysis demonstrated no significant difference in side effects between the 2 drugs.1
Steroids help, but concomitant antibiotics muddy the data
A meta-analysis of 8 RCTs enrolling 743 patients (369 children and 374 adults) found that oral and intramuscular steroids reduce duration and intensity of pain in moderate to severe pharyngitis and exudative pharyngitis.3 Four of the studies showed that corticosteroids completely resolve pain at 24 hours compared with placebo (number needed to treat [NNT]=3.7; 95% confidence interval [CI], 2.8-5.9), and 3 studies demonstrated pain relief at 48 hours (NNT=3.3; 95% CI, 2.4-5.6).
Although time to pain resolution varied among the studies, the research demonstrated a decrease in mean onset of pain relief by 6 hours compared with placebo (95% CI, 3.4-9.3; P<.001).3 All of the studies in the meta-analysis were limited by the fact that steroids were given in combination with antibiotics.
Demulcents have short-lived effect with a boost from anesthetics
A multicenter, prospective, randomized, double-blinded, placebo-controlled study (N=60) showed that demulcents provide short-term pain relief. On combined self-reported pain scales at 5, 10, 15, and 30 minutes, herbal tea demulcents were more effective than placebo (mean improvement in overall pain score=66.7 ± 39.2 on a 150-point scale, compared with 48.7 ± 32.8; P=.031). No difference was seen after 30 minutes.4
Demulcents with added anesthetics provide superior pain relief compared to placebo, as measured on a visual analog scale. In a single-center, randomized, double-blinded, placebo-controlled phase III study (N=240), patients who reported meaningful pain relief with lidocaine lozenges compared with placebo showed benefit from both single doses (38.3% lozenges vs 11.7% placebo; NNT=3.8) and multiple doses (73.3% lozenges vs 34.2% placebo; NNT=2.5). Additionally, pain relief lasted for >2 hours per lozenge. They also experienced more rapid onset of relief (24 minutes on average compared with 41 minutes).5
Antibiotics work better in patients with strep
A Cochrane review comparing antibiotics with placebo for sore throat showed an NNT of 5.8 (relative risk [RR]=0.68; 95% CI, 0.59-0.79) for pain resolution by Day 3 and an NNT of 21 (RR=0.49; 95% CI, 0.32-0.76) for pain resolution by Day 7. Antibiotics reduced pain more effectively in patients who tested positive for Streptococcus (RR=0.58; 95% CI, 0.48-0.71) than patients who tested negative (RR=0.78; 95% CI 0.63-0.97).6
Don’t bother with herbals or zinc
A Cochrane review of 7 RCTs of Chinese herbal remedies for sore throat pain found poor-quality methodology and thus, couldn’t recommend their use.7
A Cochrane review of zinc supplementation (13 therapeutic trials [N=966] and 2 preventive trials [N=394]) showed no significant improvement in pharyngitis symptoms compared with placebo, although zinc decreases the duration of the common cold, if taken within the first 24 hours of cold onset (standardized mean difference, -0.97; 95% CI, -1.56 to -0.38; P=.001).8 More patients in the intervention group experienced side effects (bad taste and nausea).
Recommendations
A primary care review article in the New England Journal of Medicine recommended acetaminophen as the drug of choice, while noting that ibuprofen has been shown in some studies to be more effective.9 The authors also recommended anesthetic gargles or lozenges. Antibiotics should be used in medical management only to prevent complications from Streptococcus-antigen-confirmed pharyngitis, they say.
Treatments recommended by the Institute for Clinical Systems Improvement include acetaminophen or ibuprofen, throat lozenges or hard candy, gargling with salt water (¼ tsp salt per 8 oz water), eating soft foods and frozen desserts, drinking cool or warm liquids, and antibiotics for bacterial infections.10
1. Pierce CA. Efficacy and safety of ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review. Ann Pharmacother. 2010;44:489-506.
2. Schachtel BP, Fillingim JM, Thoden WR, et al. Sore throat pain in the evaluation of mild analgesics. Clin Pharmacol Ther. 1988;44:704-711.
3. Hayward G, Thompson M, Heneghan C, et al. Corticosteroids for pain relief in sore throat: systemic review and metaanalysis. BMJ. 2009;339:b2976.-
4. Brinckmann J, Sigwart H, van Houten L Taylor. Safety and efficacy of a traditional herbal medicine (Throat Coat) in symptomatic temporary relief of pain in patients with acute pharyngitis: a multicenter, prospective, randomized, double-blinded, placebo-controlled study. J Altern Complement Med. 2003;9:285-298.
5. Wonnemann M, Helm I, Strauss-Grabo M, et al. Lidocaine 8 mg sore throat lozenges in the treatment of acute pharyngitis. A new therapeutic option investigated in comparison to placebo treatment. Arznelmittelforschung. 2007;57:689-697.
6. Spinks A, Glasziou PP, Del Mar C. Antibiotics for sore throat. Cochrane Database Syst Rev. 2010;(2):CD000023.-
7. Shi Y, Gu R, Liu C, et al. Chinese medicinal herbs for sore throat. Cochrane Database Syst Rev. 2010;(3):CD004877.-
8. Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev. 2011;(2):CD001364.-
9. Bisno AL. Acute pharyngitis. N Engl J Med. 2001;344:201-211.
10. Institute for Clinical Systems Improvement. Diagnosis and treatment of respiratory illness in children and adults. Available at: www.icsi.org/guidelines_and_more/gl_os_prot/respiratory/respiratory_illness_in_children_and_adults__guideline_/respiratory_illness_in_children_and_adults__guideline__13110.html. Accessed February 10, 2011.
1. Pierce CA. Efficacy and safety of ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review. Ann Pharmacother. 2010;44:489-506.
2. Schachtel BP, Fillingim JM, Thoden WR, et al. Sore throat pain in the evaluation of mild analgesics. Clin Pharmacol Ther. 1988;44:704-711.
3. Hayward G, Thompson M, Heneghan C, et al. Corticosteroids for pain relief in sore throat: systemic review and metaanalysis. BMJ. 2009;339:b2976.-
4. Brinckmann J, Sigwart H, van Houten L Taylor. Safety and efficacy of a traditional herbal medicine (Throat Coat) in symptomatic temporary relief of pain in patients with acute pharyngitis: a multicenter, prospective, randomized, double-blinded, placebo-controlled study. J Altern Complement Med. 2003;9:285-298.
5. Wonnemann M, Helm I, Strauss-Grabo M, et al. Lidocaine 8 mg sore throat lozenges in the treatment of acute pharyngitis. A new therapeutic option investigated in comparison to placebo treatment. Arznelmittelforschung. 2007;57:689-697.
6. Spinks A, Glasziou PP, Del Mar C. Antibiotics for sore throat. Cochrane Database Syst Rev. 2010;(2):CD000023.-
7. Shi Y, Gu R, Liu C, et al. Chinese medicinal herbs for sore throat. Cochrane Database Syst Rev. 2010;(3):CD004877.-
8. Singh M, Das RR. Zinc for the common cold. Cochrane Database Syst Rev. 2011;(2):CD001364.-
9. Bisno AL. Acute pharyngitis. N Engl J Med. 2001;344:201-211.
10. Institute for Clinical Systems Improvement. Diagnosis and treatment of respiratory illness in children and adults. Available at: www.icsi.org/guidelines_and_more/gl_os_prot/respiratory/respiratory_illness_in_children_and_adults__guideline_/respiratory_illness_in_children_and_adults__guideline__13110.html. Accessed February 10, 2011.
Evidence-based answers from the Family Physicians Inquiries Network
Which oral antibiotics are best for acne?
DOXYCYCLINE IS EFFECTIVE (strength of recommendation [SOR]: B, randomized controlled trial) and the antibiotic of choice (SOR: C, expert opinion) for moderate to severe inflammatory acne requiring oral treatment. Limiting side effects include photosensitivity and gastrointestinal (GI) disturbance.
Other members of the tetracycline family are considered second-line agents because of their side-effect profile and are contraindicated in pregnancy and for children younger than 12 years (SOR: A, meta-analysis, and C, expert opinion). For these patients, erythromycin is effective and better studied than azithromycin (SOR: C, expert opinion). Otherwise, emerging resistance and GI disturbances make erythromycin a third-line treatment.
The use of oral antibiotics should be limited to moderate to severe inflammatory acne unresponsive to topical therapies, including retinoids and antibiotics (SOR: C, expert opinion). Oral antibiotics should be used for at least 6 to 8 weeks and discontinued after 12 to 18 weeks of therapy (SOR: C, expert opinion).
Evidence summary
Acne vulgaris is an extremely common disorder affecting up to 95% of adolescents.1 Doxycycline improves inflammatory lesions and has a tolerable side-effect profile.
Doxycycline: Fewer lesions, few side effects
A 2003 randomized, double-blind, controlled trial of 51 patients demonstrated that a subantimicrobial dose of doxycycline (20 mg orally twice a day) reduced comedonal lesions by 53.2% (from 31 to 16; P=.04) and inflammatory lesions by 50.1% (from 55 to 25; P<.01), whereas placebo decreased comedonal lesions by 10.6% (from 51 to 46; P=.4) and inflammatory lesions by 30.2% (from 27 to 19; P<.01).2
The most commonly reported adverse effects of doxycycline are GI disturbance and sensitivity to ultraviolet radiation (sunlight). A recent systematic review found an adverse event rate of 13 per 1 million prescriptions written.3
Minocycline: Probably effective, but not the first choice
A 2003 Cochrane review examined 27 randomized trials that compared oral minocycline with placebo or other active treatments, including topical and systemic antibiotics, in a total of 3031 patients with acne vulgaris on the face or upper trunk.4 The review determined that minocycline is probably an effective treatment for moderate acne vulgaris. However, no reliable evidence from randomized controlled trials (RCTs) justifies its use as a first-line agent, especially given its higher cost relative to other treatments.
Drug resistance weakens macrolides’ “punch”
Macrolide antibiotics, primarily erythromycin, were at one time considered first-line treatment for acne, but have fallen out of favor because of emerging drug resistance. Nevertheless, erythromycin’s price and safety in pregnant women and young children has maintained its standing in acne therapy. A 1986 RCT that compared erythromycin with tetracycline found comparable efficacy: a 65% reduction in papules, from 21 to 12 lesions, for erythromycin and a 62% reduction, from 17 to 10 lesions, for tetracycline (P<.0001).5 The main side effect of macrolide antibiotics is GI disturbance.
A 2006 RCT randomized 290 patients to the macrolide azithromycin (500 mg daily for 3 consecutive days a week in the first month, then 250 mg every other day for 2 months) or tetracycline (1 g daily for 1 month, then 500 mg daily for 2 months). The drugs produced comparable results: an 84.7% improvement with azithromycin and a 79.7% improvement with tetracycline (P<.05).6 Compared with other macrolides and tetracycline, azithromycin has a more tolerable side-effect profile with fewer GI disturbances.
Lack of sufficient data on trimethoprim±sulfamethoxazole, fluoroquinolones, and cephalosporins precludes their inclusion in routine acne treatment.
Recommendations
The American Academy of Pediatrics (AAP) recommends topical retinoids as the foundation of treatment for most acne patients, and a topical microbial agent for additional therapy. Oral antibiotics should be reserved for moderate to severe inflammatory acne; tetracyclines are the standard first-line choice in most cases. The AAP warns against giving tetracyclines to children younger than 10 years because of the risk of permanent discoloration of teeth and abnormal skeletal development.7,8
The American Academy of Dermatology also recommends topical retinoids as first-line therapy for acne followed by oral doxycycline or minocycline if needed. Erythromycin is recommended for patients who can’t use tetracyclines, but with a warning about possible bacterial resistance.9
TABLE 1 shows the cost of various acne medications. TABLE 2 outlines their safety and risk profiles.
TABLE 1
Estimated cost of oral acne medications
| Medication | Dose, formulation, and frequency | Cost of 30-day supply* |
|---|---|---|
| Doxycycline hyclate | 100 mg capsule daily | $12.99 |
| Doxycycline hyclate | 100 mg tablet daily | $20.99 |
| Extended-release minocycline | 45 mg tablet daily | $450.97 |
| Minocycline | 100 mg capsule twice a day | $45.98 |
| Minocycline | 100 mg tablet twice a day | $227.98 |
| Erythromycin base | 250 mg enteric-coated capsule 4 times a day | $154.62 |
| Erythromycin base | 250 mg tablet 4 times a day | $114.62 |
| Azithromycin | 500 mg tablet daily, 3 days/wk | $175.20 |
| *http://www.drugstore.com. Accessed April 10, 2011. | ||
TABLE 2
Safety and adverse-effect profiles of acne medications8
| Medication | Adverse effects | Pregnancy category | Lactation safety | Appropriate age range |
|---|---|---|---|---|
| Doxycycline hyclate | Photosensitivity, GI disturbance, elevated BUN | D | Avoid | >12 y |
| Minocycline | Tooth discoloration, dizziness, hypersensitivity syndrome | D | Avoid; milk effects possible | >12 y |
| Erythromycin base | GI disturbance, nausea | B | Safe | FDA-approved for children |
| Azithromycin | Abdominal pain, GI disturbance | B | Minimal risk | Extended-release formula not FDA-approved for children |
| BUN, blood urea nitrogen; GI, gastrointestinal. | ||||
1. Amin K, Riddle CC, Aires DJ, et al. Common and alternate oral antibiotic therapies for acne vulgaris: a review. J Drugs Dermatol. 2007;6:873-880.
2. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol. 2003;139:459-464.
3. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther. 2005;27:1329-1342.
4. Garner SE, Eady EA, Popescu C, et al. Minocycline for acne vulgaris: efficacy and safety. Cochrane Database Syst Rev. 2003;(1):CD002086.-
5. Gammon WR, Meyer C, Lantis S, et al. Comparative efficacy of oral erythromycin versus oral tetracycline in the treatment of acne vulgaris. A double-blind study. J Am Acad Dermatol. 1986;14:183-186.
6. Rafiei R, Yaghoobi R. Azithromycin versus tetracycline in the treatment of acne vulgaris. J Dermatol Treat. 2006;17:217-221.
7. Hurwitz S. Acne vulgaris: pathogenesis and management. Pediatr Rev. 1994;15:47-52.
8. Zaenglein AL, Thiboutot DM. Expert committee recommendations for acne management. Pediatrics. 2006;118:1188-1199.
9. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol. 2007;56:651-663.
DOXYCYCLINE IS EFFECTIVE (strength of recommendation [SOR]: B, randomized controlled trial) and the antibiotic of choice (SOR: C, expert opinion) for moderate to severe inflammatory acne requiring oral treatment. Limiting side effects include photosensitivity and gastrointestinal (GI) disturbance.
Other members of the tetracycline family are considered second-line agents because of their side-effect profile and are contraindicated in pregnancy and for children younger than 12 years (SOR: A, meta-analysis, and C, expert opinion). For these patients, erythromycin is effective and better studied than azithromycin (SOR: C, expert opinion). Otherwise, emerging resistance and GI disturbances make erythromycin a third-line treatment.
The use of oral antibiotics should be limited to moderate to severe inflammatory acne unresponsive to topical therapies, including retinoids and antibiotics (SOR: C, expert opinion). Oral antibiotics should be used for at least 6 to 8 weeks and discontinued after 12 to 18 weeks of therapy (SOR: C, expert opinion).
Evidence summary
Acne vulgaris is an extremely common disorder affecting up to 95% of adolescents.1 Doxycycline improves inflammatory lesions and has a tolerable side-effect profile.
Doxycycline: Fewer lesions, few side effects
A 2003 randomized, double-blind, controlled trial of 51 patients demonstrated that a subantimicrobial dose of doxycycline (20 mg orally twice a day) reduced comedonal lesions by 53.2% (from 31 to 16; P=.04) and inflammatory lesions by 50.1% (from 55 to 25; P<.01), whereas placebo decreased comedonal lesions by 10.6% (from 51 to 46; P=.4) and inflammatory lesions by 30.2% (from 27 to 19; P<.01).2
The most commonly reported adverse effects of doxycycline are GI disturbance and sensitivity to ultraviolet radiation (sunlight). A recent systematic review found an adverse event rate of 13 per 1 million prescriptions written.3
Minocycline: Probably effective, but not the first choice
A 2003 Cochrane review examined 27 randomized trials that compared oral minocycline with placebo or other active treatments, including topical and systemic antibiotics, in a total of 3031 patients with acne vulgaris on the face or upper trunk.4 The review determined that minocycline is probably an effective treatment for moderate acne vulgaris. However, no reliable evidence from randomized controlled trials (RCTs) justifies its use as a first-line agent, especially given its higher cost relative to other treatments.
Drug resistance weakens macrolides’ “punch”
Macrolide antibiotics, primarily erythromycin, were at one time considered first-line treatment for acne, but have fallen out of favor because of emerging drug resistance. Nevertheless, erythromycin’s price and safety in pregnant women and young children has maintained its standing in acne therapy. A 1986 RCT that compared erythromycin with tetracycline found comparable efficacy: a 65% reduction in papules, from 21 to 12 lesions, for erythromycin and a 62% reduction, from 17 to 10 lesions, for tetracycline (P<.0001).5 The main side effect of macrolide antibiotics is GI disturbance.
A 2006 RCT randomized 290 patients to the macrolide azithromycin (500 mg daily for 3 consecutive days a week in the first month, then 250 mg every other day for 2 months) or tetracycline (1 g daily for 1 month, then 500 mg daily for 2 months). The drugs produced comparable results: an 84.7% improvement with azithromycin and a 79.7% improvement with tetracycline (P<.05).6 Compared with other macrolides and tetracycline, azithromycin has a more tolerable side-effect profile with fewer GI disturbances.
Lack of sufficient data on trimethoprim±sulfamethoxazole, fluoroquinolones, and cephalosporins precludes their inclusion in routine acne treatment.
Recommendations
The American Academy of Pediatrics (AAP) recommends topical retinoids as the foundation of treatment for most acne patients, and a topical microbial agent for additional therapy. Oral antibiotics should be reserved for moderate to severe inflammatory acne; tetracyclines are the standard first-line choice in most cases. The AAP warns against giving tetracyclines to children younger than 10 years because of the risk of permanent discoloration of teeth and abnormal skeletal development.7,8
The American Academy of Dermatology also recommends topical retinoids as first-line therapy for acne followed by oral doxycycline or minocycline if needed. Erythromycin is recommended for patients who can’t use tetracyclines, but with a warning about possible bacterial resistance.9
TABLE 1 shows the cost of various acne medications. TABLE 2 outlines their safety and risk profiles.
TABLE 1
Estimated cost of oral acne medications
| Medication | Dose, formulation, and frequency | Cost of 30-day supply* |
|---|---|---|
| Doxycycline hyclate | 100 mg capsule daily | $12.99 |
| Doxycycline hyclate | 100 mg tablet daily | $20.99 |
| Extended-release minocycline | 45 mg tablet daily | $450.97 |
| Minocycline | 100 mg capsule twice a day | $45.98 |
| Minocycline | 100 mg tablet twice a day | $227.98 |
| Erythromycin base | 250 mg enteric-coated capsule 4 times a day | $154.62 |
| Erythromycin base | 250 mg tablet 4 times a day | $114.62 |
| Azithromycin | 500 mg tablet daily, 3 days/wk | $175.20 |
| *http://www.drugstore.com. Accessed April 10, 2011. | ||
TABLE 2
Safety and adverse-effect profiles of acne medications8
| Medication | Adverse effects | Pregnancy category | Lactation safety | Appropriate age range |
|---|---|---|---|---|
| Doxycycline hyclate | Photosensitivity, GI disturbance, elevated BUN | D | Avoid | >12 y |
| Minocycline | Tooth discoloration, dizziness, hypersensitivity syndrome | D | Avoid; milk effects possible | >12 y |
| Erythromycin base | GI disturbance, nausea | B | Safe | FDA-approved for children |
| Azithromycin | Abdominal pain, GI disturbance | B | Minimal risk | Extended-release formula not FDA-approved for children |
| BUN, blood urea nitrogen; GI, gastrointestinal. | ||||
DOXYCYCLINE IS EFFECTIVE (strength of recommendation [SOR]: B, randomized controlled trial) and the antibiotic of choice (SOR: C, expert opinion) for moderate to severe inflammatory acne requiring oral treatment. Limiting side effects include photosensitivity and gastrointestinal (GI) disturbance.
Other members of the tetracycline family are considered second-line agents because of their side-effect profile and are contraindicated in pregnancy and for children younger than 12 years (SOR: A, meta-analysis, and C, expert opinion). For these patients, erythromycin is effective and better studied than azithromycin (SOR: C, expert opinion). Otherwise, emerging resistance and GI disturbances make erythromycin a third-line treatment.
The use of oral antibiotics should be limited to moderate to severe inflammatory acne unresponsive to topical therapies, including retinoids and antibiotics (SOR: C, expert opinion). Oral antibiotics should be used for at least 6 to 8 weeks and discontinued after 12 to 18 weeks of therapy (SOR: C, expert opinion).
Evidence summary
Acne vulgaris is an extremely common disorder affecting up to 95% of adolescents.1 Doxycycline improves inflammatory lesions and has a tolerable side-effect profile.
Doxycycline: Fewer lesions, few side effects
A 2003 randomized, double-blind, controlled trial of 51 patients demonstrated that a subantimicrobial dose of doxycycline (20 mg orally twice a day) reduced comedonal lesions by 53.2% (from 31 to 16; P=.04) and inflammatory lesions by 50.1% (from 55 to 25; P<.01), whereas placebo decreased comedonal lesions by 10.6% (from 51 to 46; P=.4) and inflammatory lesions by 30.2% (from 27 to 19; P<.01).2
The most commonly reported adverse effects of doxycycline are GI disturbance and sensitivity to ultraviolet radiation (sunlight). A recent systematic review found an adverse event rate of 13 per 1 million prescriptions written.3
Minocycline: Probably effective, but not the first choice
A 2003 Cochrane review examined 27 randomized trials that compared oral minocycline with placebo or other active treatments, including topical and systemic antibiotics, in a total of 3031 patients with acne vulgaris on the face or upper trunk.4 The review determined that minocycline is probably an effective treatment for moderate acne vulgaris. However, no reliable evidence from randomized controlled trials (RCTs) justifies its use as a first-line agent, especially given its higher cost relative to other treatments.
Drug resistance weakens macrolides’ “punch”
Macrolide antibiotics, primarily erythromycin, were at one time considered first-line treatment for acne, but have fallen out of favor because of emerging drug resistance. Nevertheless, erythromycin’s price and safety in pregnant women and young children has maintained its standing in acne therapy. A 1986 RCT that compared erythromycin with tetracycline found comparable efficacy: a 65% reduction in papules, from 21 to 12 lesions, for erythromycin and a 62% reduction, from 17 to 10 lesions, for tetracycline (P<.0001).5 The main side effect of macrolide antibiotics is GI disturbance.
A 2006 RCT randomized 290 patients to the macrolide azithromycin (500 mg daily for 3 consecutive days a week in the first month, then 250 mg every other day for 2 months) or tetracycline (1 g daily for 1 month, then 500 mg daily for 2 months). The drugs produced comparable results: an 84.7% improvement with azithromycin and a 79.7% improvement with tetracycline (P<.05).6 Compared with other macrolides and tetracycline, azithromycin has a more tolerable side-effect profile with fewer GI disturbances.
Lack of sufficient data on trimethoprim±sulfamethoxazole, fluoroquinolones, and cephalosporins precludes their inclusion in routine acne treatment.
Recommendations
The American Academy of Pediatrics (AAP) recommends topical retinoids as the foundation of treatment for most acne patients, and a topical microbial agent for additional therapy. Oral antibiotics should be reserved for moderate to severe inflammatory acne; tetracyclines are the standard first-line choice in most cases. The AAP warns against giving tetracyclines to children younger than 10 years because of the risk of permanent discoloration of teeth and abnormal skeletal development.7,8
The American Academy of Dermatology also recommends topical retinoids as first-line therapy for acne followed by oral doxycycline or minocycline if needed. Erythromycin is recommended for patients who can’t use tetracyclines, but with a warning about possible bacterial resistance.9
TABLE 1 shows the cost of various acne medications. TABLE 2 outlines their safety and risk profiles.
TABLE 1
Estimated cost of oral acne medications
| Medication | Dose, formulation, and frequency | Cost of 30-day supply* |
|---|---|---|
| Doxycycline hyclate | 100 mg capsule daily | $12.99 |
| Doxycycline hyclate | 100 mg tablet daily | $20.99 |
| Extended-release minocycline | 45 mg tablet daily | $450.97 |
| Minocycline | 100 mg capsule twice a day | $45.98 |
| Minocycline | 100 mg tablet twice a day | $227.98 |
| Erythromycin base | 250 mg enteric-coated capsule 4 times a day | $154.62 |
| Erythromycin base | 250 mg tablet 4 times a day | $114.62 |
| Azithromycin | 500 mg tablet daily, 3 days/wk | $175.20 |
| *http://www.drugstore.com. Accessed April 10, 2011. | ||
TABLE 2
Safety and adverse-effect profiles of acne medications8
| Medication | Adverse effects | Pregnancy category | Lactation safety | Appropriate age range |
|---|---|---|---|---|
| Doxycycline hyclate | Photosensitivity, GI disturbance, elevated BUN | D | Avoid | >12 y |
| Minocycline | Tooth discoloration, dizziness, hypersensitivity syndrome | D | Avoid; milk effects possible | >12 y |
| Erythromycin base | GI disturbance, nausea | B | Safe | FDA-approved for children |
| Azithromycin | Abdominal pain, GI disturbance | B | Minimal risk | Extended-release formula not FDA-approved for children |
| BUN, blood urea nitrogen; GI, gastrointestinal. | ||||
1. Amin K, Riddle CC, Aires DJ, et al. Common and alternate oral antibiotic therapies for acne vulgaris: a review. J Drugs Dermatol. 2007;6:873-880.
2. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol. 2003;139:459-464.
3. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther. 2005;27:1329-1342.
4. Garner SE, Eady EA, Popescu C, et al. Minocycline for acne vulgaris: efficacy and safety. Cochrane Database Syst Rev. 2003;(1):CD002086.-
5. Gammon WR, Meyer C, Lantis S, et al. Comparative efficacy of oral erythromycin versus oral tetracycline in the treatment of acne vulgaris. A double-blind study. J Am Acad Dermatol. 1986;14:183-186.
6. Rafiei R, Yaghoobi R. Azithromycin versus tetracycline in the treatment of acne vulgaris. J Dermatol Treat. 2006;17:217-221.
7. Hurwitz S. Acne vulgaris: pathogenesis and management. Pediatr Rev. 1994;15:47-52.
8. Zaenglein AL, Thiboutot DM. Expert committee recommendations for acne management. Pediatrics. 2006;118:1188-1199.
9. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol. 2007;56:651-663.
1. Amin K, Riddle CC, Aires DJ, et al. Common and alternate oral antibiotic therapies for acne vulgaris: a review. J Drugs Dermatol. 2007;6:873-880.
2. Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol. 2003;139:459-464.
3. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther. 2005;27:1329-1342.
4. Garner SE, Eady EA, Popescu C, et al. Minocycline for acne vulgaris: efficacy and safety. Cochrane Database Syst Rev. 2003;(1):CD002086.-
5. Gammon WR, Meyer C, Lantis S, et al. Comparative efficacy of oral erythromycin versus oral tetracycline in the treatment of acne vulgaris. A double-blind study. J Am Acad Dermatol. 1986;14:183-186.
6. Rafiei R, Yaghoobi R. Azithromycin versus tetracycline in the treatment of acne vulgaris. J Dermatol Treat. 2006;17:217-221.
7. Hurwitz S. Acne vulgaris: pathogenesis and management. Pediatr Rev. 1994;15:47-52.
8. Zaenglein AL, Thiboutot DM. Expert committee recommendations for acne management. Pediatrics. 2006;118:1188-1199.
9. Strauss JS, Krowchuk DP, Leyden JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol. 2007;56:651-663.
Evidence-based answers from the Family Physicians Inquiries Network
What are the adverse effects of prolonged opioid use in patients with chronic pain?
CONSTIPATION, NAUSEA, AND DYSPEPSIA are the most common long-term adverse effects of chronic opioid use (strength of recommendation [SOR]: B, systematic review of low-quality studies). Men may experience depression, fatigue, and sexual dysfunction (SOR: B, 2 observational studies). Prolonged use of opioids also may increase sensitivity to pain (SOR: C, review of case reports and case series). (This review does not address drug seeking or drug escalating.)
Patients on long-term methadone are at risk for cardiac arrhythmias caused by prolonged QT intervals and torsades de pointes (SOR: C, case reports).
Patients taking buprenorphine for opioid dependence may experience acute hepatitis (SOR: C, 1 case report).
Evidence summary
Chronic pain is usually defined as pain persisting longer than 3 months. Evidence of the efficacy of opioids for noncancer pain has led to increased opioid prescribing over the past 20 years and with it, growing concern about adverse effects from long-term use.1
Nausea, constipation, dyspepsia lead side-effects parade
A Cochrane systematic review of 26 studies (25 observational studies and 1 randomized controlled trial [RCT]) of adults who had taken opioids for noncancer pain for at least 6 months assessed the adverse effects of long-term opioid therapy.2 Although the authors couldn’t quantify the incidence of adverse effects because of inconsistent reporting and definition of effects, they stated that the most common complications were nausea, constipation, and dyspepsia. The review found that 22.9% of patients (95% confidence interval [CI], 15.3-32.8) discontinued oral opioids because of adverse effects.
A cross-sectional observational study evaluated self-reported adverse effects in 889 patients who received opioid therapy for noncancer pain lasting at least 3 months.3 Forty percent of patients reported constipation and 18% sexual dysfunction. Patients taking opioids daily experienced more constipation than patients taking the drugs intermittently (39% vs 24%; number needed to harm [NNH]=7; P<.05).
Sexual dysfunction, fatigue, depression aren’t far behind
A case-control study of 20 male cancer survivors with neuropathic pain who took 200 mg of morphine-equivalent daily for a year found that 90% of patients in the opioid group experienced hypogonadism with symptoms of sexual dysfunction, fatigue, and depression, compared with 40% of the 20 controls (NNH=2; 95% CI, 1-5).4
A case-controlled observational study of 54 men with noncancer pain who took opioids for 1 year found that 39 of 45 men who had normal erectile function before opioid therapy reported severe erectile dysfunction while taking the drugs.5 Levels of testosterone and estradiol were significantly lower (P<.0001) in the men taking opioids than the 27 opioid-free controls.
Potentially fatal arrhythmias are a risk for some patients
From 1969 to 2002, 59 cases of QT prolongation or torsades de pointes in methadone users, 5 (8.5%) of them fatal, were reported to the US Food and Drug Administration’s Medwatch Database.6 The mean daily methadone dose was 410 mg (median dose 345 mg, range 29-1680 mg). Length of therapy was not reported. In 44 (75%) of reported cases, patients had other known risks for QT prolongation or torsades de pointes, including female sex, interacting medications, potassium or magnesium abnormalities, and structural heart disease.
Buprenorphine may cause acute hepatitis
No apparent long-term hepatic adverse effects are associated with chronic opioid use. However, a 2004 case series described acute cytolytic hepatitis in 7 patients taking buprenorphine, all with hepatitis C and a history of intravenous drug abuse.7 Acute symptoms resolved quickly in all cases, and only 3 patients required a reduction in buprenorphine dosage.
Prolonged use may increase sensitivity to pain
Case reports and case series have found that prolonged use of opioids causes increased sensitivity to pain in some patients, which is difficult to differentiate from opioid tolerance.8
Recommendations
The American Pain Society (APS) recommends anticipating, identifying, and treating opioid-related adverse effects such as constipation or nausea.1 APS advises against using opioid antagonists to prevent or treat bowel dysfunction, and encourages older patients or patients with an increased risk of developing constipation to start a bowel regimen. Patients with complaints suggesting hypogonadism should be tested for hormonal deficiencies.
The Center for Substance Abuse and Treatment recommends obtaining a cardiac history and an electrocardiogram (EKG) on all patients before starting methadone and repeating the EKG at 30 days and annually thereafter to evaluate for QT prolongation.9 Prescribers should also warn patients of the risk of methadone-induced arrhythmias and be aware of interacting medications that prolong the QT interval or reduce methadone elimination.
1. Chou R, Fanciullo GJ, Adler JA, et al. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. J Pain. 2009;10:113-130.
2. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;(1):CD006605.-
3. Brown RT, Zuelsdorff M, Fleming M. Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag. 2006;2:137-146.
4. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004;100:851-858.
5. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377-384.
6. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf. 2005;14:747-753.
7. Hervé S, Riachi G, Noblet C, et al. Acute hepatitis due to buprenorphine administration. Eur J Gastroenterol Hepatol. 2004;16:1033-1037.
8. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med. 2003;20:1943-1953.
9. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.
CONSTIPATION, NAUSEA, AND DYSPEPSIA are the most common long-term adverse effects of chronic opioid use (strength of recommendation [SOR]: B, systematic review of low-quality studies). Men may experience depression, fatigue, and sexual dysfunction (SOR: B, 2 observational studies). Prolonged use of opioids also may increase sensitivity to pain (SOR: C, review of case reports and case series). (This review does not address drug seeking or drug escalating.)
Patients on long-term methadone are at risk for cardiac arrhythmias caused by prolonged QT intervals and torsades de pointes (SOR: C, case reports).
Patients taking buprenorphine for opioid dependence may experience acute hepatitis (SOR: C, 1 case report).
Evidence summary
Chronic pain is usually defined as pain persisting longer than 3 months. Evidence of the efficacy of opioids for noncancer pain has led to increased opioid prescribing over the past 20 years and with it, growing concern about adverse effects from long-term use.1
Nausea, constipation, dyspepsia lead side-effects parade
A Cochrane systematic review of 26 studies (25 observational studies and 1 randomized controlled trial [RCT]) of adults who had taken opioids for noncancer pain for at least 6 months assessed the adverse effects of long-term opioid therapy.2 Although the authors couldn’t quantify the incidence of adverse effects because of inconsistent reporting and definition of effects, they stated that the most common complications were nausea, constipation, and dyspepsia. The review found that 22.9% of patients (95% confidence interval [CI], 15.3-32.8) discontinued oral opioids because of adverse effects.
A cross-sectional observational study evaluated self-reported adverse effects in 889 patients who received opioid therapy for noncancer pain lasting at least 3 months.3 Forty percent of patients reported constipation and 18% sexual dysfunction. Patients taking opioids daily experienced more constipation than patients taking the drugs intermittently (39% vs 24%; number needed to harm [NNH]=7; P<.05).
Sexual dysfunction, fatigue, depression aren’t far behind
A case-control study of 20 male cancer survivors with neuropathic pain who took 200 mg of morphine-equivalent daily for a year found that 90% of patients in the opioid group experienced hypogonadism with symptoms of sexual dysfunction, fatigue, and depression, compared with 40% of the 20 controls (NNH=2; 95% CI, 1-5).4
A case-controlled observational study of 54 men with noncancer pain who took opioids for 1 year found that 39 of 45 men who had normal erectile function before opioid therapy reported severe erectile dysfunction while taking the drugs.5 Levels of testosterone and estradiol were significantly lower (P<.0001) in the men taking opioids than the 27 opioid-free controls.
Potentially fatal arrhythmias are a risk for some patients
From 1969 to 2002, 59 cases of QT prolongation or torsades de pointes in methadone users, 5 (8.5%) of them fatal, were reported to the US Food and Drug Administration’s Medwatch Database.6 The mean daily methadone dose was 410 mg (median dose 345 mg, range 29-1680 mg). Length of therapy was not reported. In 44 (75%) of reported cases, patients had other known risks for QT prolongation or torsades de pointes, including female sex, interacting medications, potassium or magnesium abnormalities, and structural heart disease.
Buprenorphine may cause acute hepatitis
No apparent long-term hepatic adverse effects are associated with chronic opioid use. However, a 2004 case series described acute cytolytic hepatitis in 7 patients taking buprenorphine, all with hepatitis C and a history of intravenous drug abuse.7 Acute symptoms resolved quickly in all cases, and only 3 patients required a reduction in buprenorphine dosage.
Prolonged use may increase sensitivity to pain
Case reports and case series have found that prolonged use of opioids causes increased sensitivity to pain in some patients, which is difficult to differentiate from opioid tolerance.8
Recommendations
The American Pain Society (APS) recommends anticipating, identifying, and treating opioid-related adverse effects such as constipation or nausea.1 APS advises against using opioid antagonists to prevent or treat bowel dysfunction, and encourages older patients or patients with an increased risk of developing constipation to start a bowel regimen. Patients with complaints suggesting hypogonadism should be tested for hormonal deficiencies.
The Center for Substance Abuse and Treatment recommends obtaining a cardiac history and an electrocardiogram (EKG) on all patients before starting methadone and repeating the EKG at 30 days and annually thereafter to evaluate for QT prolongation.9 Prescribers should also warn patients of the risk of methadone-induced arrhythmias and be aware of interacting medications that prolong the QT interval or reduce methadone elimination.
CONSTIPATION, NAUSEA, AND DYSPEPSIA are the most common long-term adverse effects of chronic opioid use (strength of recommendation [SOR]: B, systematic review of low-quality studies). Men may experience depression, fatigue, and sexual dysfunction (SOR: B, 2 observational studies). Prolonged use of opioids also may increase sensitivity to pain (SOR: C, review of case reports and case series). (This review does not address drug seeking or drug escalating.)
Patients on long-term methadone are at risk for cardiac arrhythmias caused by prolonged QT intervals and torsades de pointes (SOR: C, case reports).
Patients taking buprenorphine for opioid dependence may experience acute hepatitis (SOR: C, 1 case report).
Evidence summary
Chronic pain is usually defined as pain persisting longer than 3 months. Evidence of the efficacy of opioids for noncancer pain has led to increased opioid prescribing over the past 20 years and with it, growing concern about adverse effects from long-term use.1
Nausea, constipation, dyspepsia lead side-effects parade
A Cochrane systematic review of 26 studies (25 observational studies and 1 randomized controlled trial [RCT]) of adults who had taken opioids for noncancer pain for at least 6 months assessed the adverse effects of long-term opioid therapy.2 Although the authors couldn’t quantify the incidence of adverse effects because of inconsistent reporting and definition of effects, they stated that the most common complications were nausea, constipation, and dyspepsia. The review found that 22.9% of patients (95% confidence interval [CI], 15.3-32.8) discontinued oral opioids because of adverse effects.
A cross-sectional observational study evaluated self-reported adverse effects in 889 patients who received opioid therapy for noncancer pain lasting at least 3 months.3 Forty percent of patients reported constipation and 18% sexual dysfunction. Patients taking opioids daily experienced more constipation than patients taking the drugs intermittently (39% vs 24%; number needed to harm [NNH]=7; P<.05).
Sexual dysfunction, fatigue, depression aren’t far behind
A case-control study of 20 male cancer survivors with neuropathic pain who took 200 mg of morphine-equivalent daily for a year found that 90% of patients in the opioid group experienced hypogonadism with symptoms of sexual dysfunction, fatigue, and depression, compared with 40% of the 20 controls (NNH=2; 95% CI, 1-5).4
A case-controlled observational study of 54 men with noncancer pain who took opioids for 1 year found that 39 of 45 men who had normal erectile function before opioid therapy reported severe erectile dysfunction while taking the drugs.5 Levels of testosterone and estradiol were significantly lower (P<.0001) in the men taking opioids than the 27 opioid-free controls.
Potentially fatal arrhythmias are a risk for some patients
From 1969 to 2002, 59 cases of QT prolongation or torsades de pointes in methadone users, 5 (8.5%) of them fatal, were reported to the US Food and Drug Administration’s Medwatch Database.6 The mean daily methadone dose was 410 mg (median dose 345 mg, range 29-1680 mg). Length of therapy was not reported. In 44 (75%) of reported cases, patients had other known risks for QT prolongation or torsades de pointes, including female sex, interacting medications, potassium or magnesium abnormalities, and structural heart disease.
Buprenorphine may cause acute hepatitis
No apparent long-term hepatic adverse effects are associated with chronic opioid use. However, a 2004 case series described acute cytolytic hepatitis in 7 patients taking buprenorphine, all with hepatitis C and a history of intravenous drug abuse.7 Acute symptoms resolved quickly in all cases, and only 3 patients required a reduction in buprenorphine dosage.
Prolonged use may increase sensitivity to pain
Case reports and case series have found that prolonged use of opioids causes increased sensitivity to pain in some patients, which is difficult to differentiate from opioid tolerance.8
Recommendations
The American Pain Society (APS) recommends anticipating, identifying, and treating opioid-related adverse effects such as constipation or nausea.1 APS advises against using opioid antagonists to prevent or treat bowel dysfunction, and encourages older patients or patients with an increased risk of developing constipation to start a bowel regimen. Patients with complaints suggesting hypogonadism should be tested for hormonal deficiencies.
The Center for Substance Abuse and Treatment recommends obtaining a cardiac history and an electrocardiogram (EKG) on all patients before starting methadone and repeating the EKG at 30 days and annually thereafter to evaluate for QT prolongation.9 Prescribers should also warn patients of the risk of methadone-induced arrhythmias and be aware of interacting medications that prolong the QT interval or reduce methadone elimination.
1. Chou R, Fanciullo GJ, Adler JA, et al. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. J Pain. 2009;10:113-130.
2. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;(1):CD006605.-
3. Brown RT, Zuelsdorff M, Fleming M. Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag. 2006;2:137-146.
4. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004;100:851-858.
5. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377-384.
6. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf. 2005;14:747-753.
7. Hervé S, Riachi G, Noblet C, et al. Acute hepatitis due to buprenorphine administration. Eur J Gastroenterol Hepatol. 2004;16:1033-1037.
8. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med. 2003;20:1943-1953.
9. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.
1. Chou R, Fanciullo GJ, Adler JA, et al. Clinical guidelines for the use of chronic opioid therapy in chronic non-cancer pain. J Pain. 2009;10:113-130.
2. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev. 2010;(1):CD006605.-
3. Brown RT, Zuelsdorff M, Fleming M. Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag. 2006;2:137-146.
4. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004;100:851-858.
5. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002;3:377-384.
6. Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiol Drug Saf. 2005;14:747-753.
7. Hervé S, Riachi G, Noblet C, et al. Acute hepatitis due to buprenorphine administration. Eur J Gastroenterol Hepatol. 2004;16:1033-1037.
8. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med. 2003;20:1943-1953.
9. Krantz MJ, Martin J, Stimmel B, et al. QTc interval screening in methadone treatment. Ann Intern Med. 2009;150:387-395.
Evidence-based answers from the Family Physicians Inquiries Network
What’s the best way to control circumcision pain in newborns?
DORSAL PENILE NERVE BLOCK (DPNB), ring block (RB), and eutectic mixture of local anesthetics (EMLA) all control pain effectively during neonatal circumcision (strength of recommendation [SOR]: A, systematic review). An RB may provide superior pain relief to DPNB and EMLA (SOR: B, limited-quality evidence).
Using a Mogen clamp reduces pain by shortening procedure time (SOR: A, randomized controlled trials [RCTs]). Effective adjuncts to pain relief include nonnutritive sucking (NNS; a pacifier without sucrose), a sucrose pacifier, and use of a padded chair (SOR: A, RCTs).
Evidence summary
Outcome assessment of neonatal pain response includes heart rate, crying time, procedure length, and behavioral distress scores. A Cochrane systematic review of 35 RCTs with a total of 1997 newborns evaluated DPNB, RB, and EMLA for pain relief during circumcision.1 All 3 methods were more effective than placebo or no treatment. Studies of DPNB reported lowered heart rates and shorter crying times than studies with EMLA vs placebo and RB vs placebo (TABLE).
This review included 2 RCTs that compared DPNB with EMLA in 133 newborns. Infants who received DPNB had significantly lower heart rates (–17 bpm; 95% confidence interval [CI], –23 to –11).1 The review concluded that DPNB is the most effective method of anesthesia during circumcision. Comparison of effect sizes between studies may be inaccurate because of different study conditions, however.
TABLE
Comparative outcomes for circumcision anesthesia
| Type of anesthesia | Decrease in heart rate (bpm) vs placebo1 | Decrease in crying time (%) vs placebo1 | Mean proportion of time crying during foreskin separation (SD)2 | Mean proportion of time crying during clamping (SD)2 | Mean heart rate change (bpm) from baseline during separation (SD)2 |
|---|---|---|---|---|---|
| DPNB | –35 (95% CI, –41 to –30) N=592 | –54% (95% CI, –64 to –44) N=592 | 0.65 (0.33) N=14 | 0.41 (0.35) N=14 | 30.9 (32.6) N=14 |
| RB | –29 (95% CI, –52 to –7) N=12 | –26.3% (95% CI, –38 to –15) N=65 | 0.54 (0.38) N=12 | 0.37 (0.24) N=12 | 20.2 (32.1) N=12 |
| EMLA | –15 (95% CI, –19 to –10) N=200 | –15.2% (95% CI, –21 to –9.3) N=200 | 0.82 (0.17) N=15 | 0.55 (0.32) N=15 | 41.4 (31.4) N=15 |
| Placebo | NA | NA | 0.98 (0.05) N=11 | 0.85 (0.21) N=11 | 53.0 (46.2) N=11 |
| bpm, beats per minute; CI, confidence interval; DPNB, dorsal penile nerve block; EMLA, eutectic mixture of local anesthetics; NA, not applicable; RB, ring block; SD, standard deviation. | |||||
Direct comparison ranks RB first, DPNB second, EMLA third
The only head-to-head comparison of DPNB, RB, EMLA, and placebo is an RCT of 52 neonates, which found that RB resulted in the shortest mean crying time during painful procedures and the lowest increase from baseline in mean heart rate during foreskin separation. DPNB was the next most effective anesthetic; EMLA, although superior to placebo, was the least effective.2
Mogen clamp shortens procedure (and pain) more than other clamps
Three small RCTs evaluated procedure time using different types of instruments for circumcision.3-5 Two RCTS, in 57 and 48 newborns, compared the Mogen clamp with the Gomco clamp. The procedure time for the Mogen clamp was 1.9 times shorter than for the Gomco clamp in the first study (7.2 ± 0.32 vs 13.9 ± 0.32 min; P=.0001) and 2.5 times shorter in the second study (1.35 ± 0.32 vs 3.48 ± 1 min), thereby decreasing duration of pain.3,4 One of the RCTs found a significantly smaller heart rate increase from baseline for the Mogen clamp (8%) than the Gomco clamp (24%).4
In an RCT of 59 newborns, procedure time was significantly shorter with the Mogen clamp (12 ± 0.9 min) vs the PlastiBell circumcision device (20 ± 1.7 min).5
Useful adjuncts: A pacifier and a comfy chair
Effective adjuncts to DPNB include NNS, a sucrose pacifier, and use of a padded chair.6,7 An RCT of 44 newborns given a DPNB found that adjunctive NNS reduced crying time to 4.2 ± 2.6 min compared with a control time of 6.3 ± 2.35 min.6
Another RCT of 80 infants, all given a DPNB, found significantly lower behavioral distress scores (on a 3-point scale, with 3 being a sustained cry) among infants using a sucrose pacifier (0.45; standard deviation [SD]=0.80; P=.002) and padded chair (0.49; SD=0.52; P=.007) compared with controls (1.12; SD=0.48; P<.001).7
Recommendations
The American Academy of Pediatrics recommends analgesia during circumcision because sufficient evidence exists that the procedure causes pain. EMLA cream, DPNB, and RB are all options; RB may provide the most effective analgesia. A sucrose pacifier and a padded chair may be effective adjuncts.8
1. Brady-Fryer B, Wiebe N, Lander JA. Pain relief for neonatal circumcision. Cochrane Database Syst Rev. 2004;(4):CD004217.-
2. Lander J, Brady-Fryer B, Metcalfe JB, et al. Comparison of ring block, dorsal penile nerve block, and topical anesthesia for neonatal circumcision: a randomized controlled trial. JAMA. 1997;278:2157-2162.
3. Kaufman GE, Cimo S, Miller LW, et al. An evaluation of the effects of sucrose on neonatal pain with 2 commonly used circumcision methods. Am J Obstet Gynecol. 2002;186:564-568.
4. Kurtis PS, DeSilva HN, Bernstein BA, et al. A comparison of the Mogen and Gomco clamps in combination with dorsal penile nerve block in minimizing the pain of neonatal circumcision. Pediatrics. 1999;103:E23.-
5. Taeusch HW, Martinez AM, Partridge JC, et al. Pain during Mogen or PlastiBell circumcision. J Perinatol. 2002;22:214-218.
6. South MM, Strauss RA, South AP, et al. The use of non-nutritive sucking to decrease the physiologic pain response during neonatal circumcision: a randomized controlled trial. Am J Obstet Gynecol. 2005;193:537-542.
7. Stang HJ, Snellman LW, Condon LM, et al. Beyond dorsal penile nerve block: a more humane circumcision. Pediatrics. 1997;100:E3.-
8. American Academy of Pediatrics Task Force on Circumcision. Circumcision policy statement. Pediatrics. 1999;103:686-693.
DORSAL PENILE NERVE BLOCK (DPNB), ring block (RB), and eutectic mixture of local anesthetics (EMLA) all control pain effectively during neonatal circumcision (strength of recommendation [SOR]: A, systematic review). An RB may provide superior pain relief to DPNB and EMLA (SOR: B, limited-quality evidence).
Using a Mogen clamp reduces pain by shortening procedure time (SOR: A, randomized controlled trials [RCTs]). Effective adjuncts to pain relief include nonnutritive sucking (NNS; a pacifier without sucrose), a sucrose pacifier, and use of a padded chair (SOR: A, RCTs).
Evidence summary
Outcome assessment of neonatal pain response includes heart rate, crying time, procedure length, and behavioral distress scores. A Cochrane systematic review of 35 RCTs with a total of 1997 newborns evaluated DPNB, RB, and EMLA for pain relief during circumcision.1 All 3 methods were more effective than placebo or no treatment. Studies of DPNB reported lowered heart rates and shorter crying times than studies with EMLA vs placebo and RB vs placebo (TABLE).
This review included 2 RCTs that compared DPNB with EMLA in 133 newborns. Infants who received DPNB had significantly lower heart rates (–17 bpm; 95% confidence interval [CI], –23 to –11).1 The review concluded that DPNB is the most effective method of anesthesia during circumcision. Comparison of effect sizes between studies may be inaccurate because of different study conditions, however.
TABLE
Comparative outcomes for circumcision anesthesia
| Type of anesthesia | Decrease in heart rate (bpm) vs placebo1 | Decrease in crying time (%) vs placebo1 | Mean proportion of time crying during foreskin separation (SD)2 | Mean proportion of time crying during clamping (SD)2 | Mean heart rate change (bpm) from baseline during separation (SD)2 |
|---|---|---|---|---|---|
| DPNB | –35 (95% CI, –41 to –30) N=592 | –54% (95% CI, –64 to –44) N=592 | 0.65 (0.33) N=14 | 0.41 (0.35) N=14 | 30.9 (32.6) N=14 |
| RB | –29 (95% CI, –52 to –7) N=12 | –26.3% (95% CI, –38 to –15) N=65 | 0.54 (0.38) N=12 | 0.37 (0.24) N=12 | 20.2 (32.1) N=12 |
| EMLA | –15 (95% CI, –19 to –10) N=200 | –15.2% (95% CI, –21 to –9.3) N=200 | 0.82 (0.17) N=15 | 0.55 (0.32) N=15 | 41.4 (31.4) N=15 |
| Placebo | NA | NA | 0.98 (0.05) N=11 | 0.85 (0.21) N=11 | 53.0 (46.2) N=11 |
| bpm, beats per minute; CI, confidence interval; DPNB, dorsal penile nerve block; EMLA, eutectic mixture of local anesthetics; NA, not applicable; RB, ring block; SD, standard deviation. | |||||
Direct comparison ranks RB first, DPNB second, EMLA third
The only head-to-head comparison of DPNB, RB, EMLA, and placebo is an RCT of 52 neonates, which found that RB resulted in the shortest mean crying time during painful procedures and the lowest increase from baseline in mean heart rate during foreskin separation. DPNB was the next most effective anesthetic; EMLA, although superior to placebo, was the least effective.2
Mogen clamp shortens procedure (and pain) more than other clamps
Three small RCTs evaluated procedure time using different types of instruments for circumcision.3-5 Two RCTS, in 57 and 48 newborns, compared the Mogen clamp with the Gomco clamp. The procedure time for the Mogen clamp was 1.9 times shorter than for the Gomco clamp in the first study (7.2 ± 0.32 vs 13.9 ± 0.32 min; P=.0001) and 2.5 times shorter in the second study (1.35 ± 0.32 vs 3.48 ± 1 min), thereby decreasing duration of pain.3,4 One of the RCTs found a significantly smaller heart rate increase from baseline for the Mogen clamp (8%) than the Gomco clamp (24%).4
In an RCT of 59 newborns, procedure time was significantly shorter with the Mogen clamp (12 ± 0.9 min) vs the PlastiBell circumcision device (20 ± 1.7 min).5
Useful adjuncts: A pacifier and a comfy chair
Effective adjuncts to DPNB include NNS, a sucrose pacifier, and use of a padded chair.6,7 An RCT of 44 newborns given a DPNB found that adjunctive NNS reduced crying time to 4.2 ± 2.6 min compared with a control time of 6.3 ± 2.35 min.6
Another RCT of 80 infants, all given a DPNB, found significantly lower behavioral distress scores (on a 3-point scale, with 3 being a sustained cry) among infants using a sucrose pacifier (0.45; standard deviation [SD]=0.80; P=.002) and padded chair (0.49; SD=0.52; P=.007) compared with controls (1.12; SD=0.48; P<.001).7
Recommendations
The American Academy of Pediatrics recommends analgesia during circumcision because sufficient evidence exists that the procedure causes pain. EMLA cream, DPNB, and RB are all options; RB may provide the most effective analgesia. A sucrose pacifier and a padded chair may be effective adjuncts.8
DORSAL PENILE NERVE BLOCK (DPNB), ring block (RB), and eutectic mixture of local anesthetics (EMLA) all control pain effectively during neonatal circumcision (strength of recommendation [SOR]: A, systematic review). An RB may provide superior pain relief to DPNB and EMLA (SOR: B, limited-quality evidence).
Using a Mogen clamp reduces pain by shortening procedure time (SOR: A, randomized controlled trials [RCTs]). Effective adjuncts to pain relief include nonnutritive sucking (NNS; a pacifier without sucrose), a sucrose pacifier, and use of a padded chair (SOR: A, RCTs).
Evidence summary
Outcome assessment of neonatal pain response includes heart rate, crying time, procedure length, and behavioral distress scores. A Cochrane systematic review of 35 RCTs with a total of 1997 newborns evaluated DPNB, RB, and EMLA for pain relief during circumcision.1 All 3 methods were more effective than placebo or no treatment. Studies of DPNB reported lowered heart rates and shorter crying times than studies with EMLA vs placebo and RB vs placebo (TABLE).
This review included 2 RCTs that compared DPNB with EMLA in 133 newborns. Infants who received DPNB had significantly lower heart rates (–17 bpm; 95% confidence interval [CI], –23 to –11).1 The review concluded that DPNB is the most effective method of anesthesia during circumcision. Comparison of effect sizes between studies may be inaccurate because of different study conditions, however.
TABLE
Comparative outcomes for circumcision anesthesia
| Type of anesthesia | Decrease in heart rate (bpm) vs placebo1 | Decrease in crying time (%) vs placebo1 | Mean proportion of time crying during foreskin separation (SD)2 | Mean proportion of time crying during clamping (SD)2 | Mean heart rate change (bpm) from baseline during separation (SD)2 |
|---|---|---|---|---|---|
| DPNB | –35 (95% CI, –41 to –30) N=592 | –54% (95% CI, –64 to –44) N=592 | 0.65 (0.33) N=14 | 0.41 (0.35) N=14 | 30.9 (32.6) N=14 |
| RB | –29 (95% CI, –52 to –7) N=12 | –26.3% (95% CI, –38 to –15) N=65 | 0.54 (0.38) N=12 | 0.37 (0.24) N=12 | 20.2 (32.1) N=12 |
| EMLA | –15 (95% CI, –19 to –10) N=200 | –15.2% (95% CI, –21 to –9.3) N=200 | 0.82 (0.17) N=15 | 0.55 (0.32) N=15 | 41.4 (31.4) N=15 |
| Placebo | NA | NA | 0.98 (0.05) N=11 | 0.85 (0.21) N=11 | 53.0 (46.2) N=11 |
| bpm, beats per minute; CI, confidence interval; DPNB, dorsal penile nerve block; EMLA, eutectic mixture of local anesthetics; NA, not applicable; RB, ring block; SD, standard deviation. | |||||
Direct comparison ranks RB first, DPNB second, EMLA third
The only head-to-head comparison of DPNB, RB, EMLA, and placebo is an RCT of 52 neonates, which found that RB resulted in the shortest mean crying time during painful procedures and the lowest increase from baseline in mean heart rate during foreskin separation. DPNB was the next most effective anesthetic; EMLA, although superior to placebo, was the least effective.2
Mogen clamp shortens procedure (and pain) more than other clamps
Three small RCTs evaluated procedure time using different types of instruments for circumcision.3-5 Two RCTS, in 57 and 48 newborns, compared the Mogen clamp with the Gomco clamp. The procedure time for the Mogen clamp was 1.9 times shorter than for the Gomco clamp in the first study (7.2 ± 0.32 vs 13.9 ± 0.32 min; P=.0001) and 2.5 times shorter in the second study (1.35 ± 0.32 vs 3.48 ± 1 min), thereby decreasing duration of pain.3,4 One of the RCTs found a significantly smaller heart rate increase from baseline for the Mogen clamp (8%) than the Gomco clamp (24%).4
In an RCT of 59 newborns, procedure time was significantly shorter with the Mogen clamp (12 ± 0.9 min) vs the PlastiBell circumcision device (20 ± 1.7 min).5
Useful adjuncts: A pacifier and a comfy chair
Effective adjuncts to DPNB include NNS, a sucrose pacifier, and use of a padded chair.6,7 An RCT of 44 newborns given a DPNB found that adjunctive NNS reduced crying time to 4.2 ± 2.6 min compared with a control time of 6.3 ± 2.35 min.6
Another RCT of 80 infants, all given a DPNB, found significantly lower behavioral distress scores (on a 3-point scale, with 3 being a sustained cry) among infants using a sucrose pacifier (0.45; standard deviation [SD]=0.80; P=.002) and padded chair (0.49; SD=0.52; P=.007) compared with controls (1.12; SD=0.48; P<.001).7
Recommendations
The American Academy of Pediatrics recommends analgesia during circumcision because sufficient evidence exists that the procedure causes pain. EMLA cream, DPNB, and RB are all options; RB may provide the most effective analgesia. A sucrose pacifier and a padded chair may be effective adjuncts.8
1. Brady-Fryer B, Wiebe N, Lander JA. Pain relief for neonatal circumcision. Cochrane Database Syst Rev. 2004;(4):CD004217.-
2. Lander J, Brady-Fryer B, Metcalfe JB, et al. Comparison of ring block, dorsal penile nerve block, and topical anesthesia for neonatal circumcision: a randomized controlled trial. JAMA. 1997;278:2157-2162.
3. Kaufman GE, Cimo S, Miller LW, et al. An evaluation of the effects of sucrose on neonatal pain with 2 commonly used circumcision methods. Am J Obstet Gynecol. 2002;186:564-568.
4. Kurtis PS, DeSilva HN, Bernstein BA, et al. A comparison of the Mogen and Gomco clamps in combination with dorsal penile nerve block in minimizing the pain of neonatal circumcision. Pediatrics. 1999;103:E23.-
5. Taeusch HW, Martinez AM, Partridge JC, et al. Pain during Mogen or PlastiBell circumcision. J Perinatol. 2002;22:214-218.
6. South MM, Strauss RA, South AP, et al. The use of non-nutritive sucking to decrease the physiologic pain response during neonatal circumcision: a randomized controlled trial. Am J Obstet Gynecol. 2005;193:537-542.
7. Stang HJ, Snellman LW, Condon LM, et al. Beyond dorsal penile nerve block: a more humane circumcision. Pediatrics. 1997;100:E3.-
8. American Academy of Pediatrics Task Force on Circumcision. Circumcision policy statement. Pediatrics. 1999;103:686-693.
1. Brady-Fryer B, Wiebe N, Lander JA. Pain relief for neonatal circumcision. Cochrane Database Syst Rev. 2004;(4):CD004217.-
2. Lander J, Brady-Fryer B, Metcalfe JB, et al. Comparison of ring block, dorsal penile nerve block, and topical anesthesia for neonatal circumcision: a randomized controlled trial. JAMA. 1997;278:2157-2162.
3. Kaufman GE, Cimo S, Miller LW, et al. An evaluation of the effects of sucrose on neonatal pain with 2 commonly used circumcision methods. Am J Obstet Gynecol. 2002;186:564-568.
4. Kurtis PS, DeSilva HN, Bernstein BA, et al. A comparison of the Mogen and Gomco clamps in combination with dorsal penile nerve block in minimizing the pain of neonatal circumcision. Pediatrics. 1999;103:E23.-
5. Taeusch HW, Martinez AM, Partridge JC, et al. Pain during Mogen or PlastiBell circumcision. J Perinatol. 2002;22:214-218.
6. South MM, Strauss RA, South AP, et al. The use of non-nutritive sucking to decrease the physiologic pain response during neonatal circumcision: a randomized controlled trial. Am J Obstet Gynecol. 2005;193:537-542.
7. Stang HJ, Snellman LW, Condon LM, et al. Beyond dorsal penile nerve block: a more humane circumcision. Pediatrics. 1997;100:E3.-
8. American Academy of Pediatrics Task Force on Circumcision. Circumcision policy statement. Pediatrics. 1999;103:686-693.
Evidence-based answers from the Family Physicians Inquiries Network
Ureteral calculi: What should you consider before intervening?
THE SIZE OF THE CALCULI, their location, and complicating factors such as infection should all be considered.
Most ureteral calculi smaller than 5 mm pass spontaneously, as do approximately half of calculi between 5 and 10 mm. Calculi larger than 10 mm are unlikely to pass without intervention. Distal calculi are more likely to pass spontaneously than calculi in mid- or proximal ureteral locations; most spontaneous passage occurs within 4 to 6 weeks (strength of recommendation [SOR]: A, prospective cohort studies).
All patients with calculi complicated by such factors as obstruction, infection, renal injury, or a single kidney require surgical consultation (SOR: C, expert opinion).
Medical expulsion therapy with alpha-blockers (usually tamsulosin) and nifedipine improves passage rates, including for some calculi larger than 10 mm (SOR: A, meta-analysis of prospective cohort studies).
Evidence summary
A meta-analysis of 5 prospective cohort studies evaluated the rate of spontaneous passage of ureteral calculi according to size. Calculi smaller than 5 mm passed spontaneously in 68% of patients (5 studies, N=224). Calculi between 5 and 10 mm passed spontaneously in 47% of patients (3 studies, N=104).1
A prospective cohort study evaluated spontaneous passage rates of ureteral calculi by size in 172 patients who were diagnosed by unenhanced helical computed tomography.2 Investigators found spontaneous passage rates of 87% for 1-mm calculi, 76% for 2- to 4-mm calculi, 60% for 5- to 7-mm calculi, 48% for 7- to 9-mm calculi, and 25% for calculi larger than 9 mm.
Spontaneous passage rates differed significantly for calculi 1 to 4 mm in size compared with calculi 5 to 7 mm in size (P<.001) and for calculi 5 to 7 mm in size compared with calculi 8 mm or larger (P<.001). Calculi in either the distal ureter or ureterovesicular junction were more likely to pass that those in the mid- or proximal ureter (75% to 79% vs 48% to 60%; P<.001).
Most smaller calculi pass in 4 to 6 weeks
Another prospective cohort study (N=75) found that most calculi pass spontaneously within 4 to 6 weeks. In 95% of patients, calculi passed within 31 days (2 mm or smaller), 40 days (2-4 mm), or 39 days (4-6 mm).3
Some cases require prompt surgery
The American Urological Association (AUA) expert panel recommends early surgical intervention, regardless of calculus size, under the following circumstances: obstruction with high-grade hydronephrosis, infection, impending renal deterioration, intractable pain, nausea and vomiting, or obstruction in a solitary or transplanted kidney.1
Medical expulsion therapy trumps waiting for distal calculi to pass
A meta-analysis comparing rates of calculus passage found that medical expulsion therapy was more effective than expectant management for patients with distal ureteral calculi. Sixteen RCTs (N=1235) evaluated alpha-antagonists (mostly tamsulosin), and 9 RCTs (N=686) evaluated nifedipine. Treat ment periods for medical expulsion therapy ranged from 30 to 60 days.
Alpha-antagonists increased expulsion rates over expectant management for calculi ranging in size from 3 to 18 mm with a mean diameter greater than 5 mm (relative risk [RR]=1.59; 95% confidence interval [CI], 1.44-1.75; number needed to treat [NNT]=3). The mean time until passage ranged from 2.7 to 14.2 days. Nifedipine also increased expulsion rates for calculi with a mean diameter larger than 5 mm, ranging in size from 3.9 to 12.8 mm (RR=1.50; 95% CI, 1.34-1.68; NNT=4).4
Recommendations
The Joint European Association of Urology/ AUA Nephrolithiasis Guideline Panel recommends observation with periodic evaluation for patients newly diagnosed with ureteral calculi smaller than 10 mm.1 Patients may be offered medical expulsion therapy to facilitate calculus passage. Surveillance should be maintained until calculi pass; intervention should be considered if calculi don’t pass spontaneously within about 30 days.
The Panel states that patients with ureteral calculi larger than 10 mm could be observed (with or without medical expulsion therapy); however, most cases will require surgical intervention.1
Acknowledgements
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Medical Department of the United States Army or the US Army Service at large.
1. European Association of Urology/American Urology Association Nephrolithiasis Guideline Panel. 2007 Guideline for the management of ureteral calculi. Available at: www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=uc. Accessed August 16, 2010.
2. Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to calculus size and location as revealed by unenhanced helical CT. Am J Roentgenol. 2002;178:101-103.
3. Miller OF, Kane CJ. Time to calculus passage for observed ureteral calculi: a guide for patient education. J Urol. 1999;162:688-691.
4. Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007;50:552-563.
THE SIZE OF THE CALCULI, their location, and complicating factors such as infection should all be considered.
Most ureteral calculi smaller than 5 mm pass spontaneously, as do approximately half of calculi between 5 and 10 mm. Calculi larger than 10 mm are unlikely to pass without intervention. Distal calculi are more likely to pass spontaneously than calculi in mid- or proximal ureteral locations; most spontaneous passage occurs within 4 to 6 weeks (strength of recommendation [SOR]: A, prospective cohort studies).
All patients with calculi complicated by such factors as obstruction, infection, renal injury, or a single kidney require surgical consultation (SOR: C, expert opinion).
Medical expulsion therapy with alpha-blockers (usually tamsulosin) and nifedipine improves passage rates, including for some calculi larger than 10 mm (SOR: A, meta-analysis of prospective cohort studies).
Evidence summary
A meta-analysis of 5 prospective cohort studies evaluated the rate of spontaneous passage of ureteral calculi according to size. Calculi smaller than 5 mm passed spontaneously in 68% of patients (5 studies, N=224). Calculi between 5 and 10 mm passed spontaneously in 47% of patients (3 studies, N=104).1
A prospective cohort study evaluated spontaneous passage rates of ureteral calculi by size in 172 patients who were diagnosed by unenhanced helical computed tomography.2 Investigators found spontaneous passage rates of 87% for 1-mm calculi, 76% for 2- to 4-mm calculi, 60% for 5- to 7-mm calculi, 48% for 7- to 9-mm calculi, and 25% for calculi larger than 9 mm.
Spontaneous passage rates differed significantly for calculi 1 to 4 mm in size compared with calculi 5 to 7 mm in size (P<.001) and for calculi 5 to 7 mm in size compared with calculi 8 mm or larger (P<.001). Calculi in either the distal ureter or ureterovesicular junction were more likely to pass that those in the mid- or proximal ureter (75% to 79% vs 48% to 60%; P<.001).
Most smaller calculi pass in 4 to 6 weeks
Another prospective cohort study (N=75) found that most calculi pass spontaneously within 4 to 6 weeks. In 95% of patients, calculi passed within 31 days (2 mm or smaller), 40 days (2-4 mm), or 39 days (4-6 mm).3
Some cases require prompt surgery
The American Urological Association (AUA) expert panel recommends early surgical intervention, regardless of calculus size, under the following circumstances: obstruction with high-grade hydronephrosis, infection, impending renal deterioration, intractable pain, nausea and vomiting, or obstruction in a solitary or transplanted kidney.1
Medical expulsion therapy trumps waiting for distal calculi to pass
A meta-analysis comparing rates of calculus passage found that medical expulsion therapy was more effective than expectant management for patients with distal ureteral calculi. Sixteen RCTs (N=1235) evaluated alpha-antagonists (mostly tamsulosin), and 9 RCTs (N=686) evaluated nifedipine. Treat ment periods for medical expulsion therapy ranged from 30 to 60 days.
Alpha-antagonists increased expulsion rates over expectant management for calculi ranging in size from 3 to 18 mm with a mean diameter greater than 5 mm (relative risk [RR]=1.59; 95% confidence interval [CI], 1.44-1.75; number needed to treat [NNT]=3). The mean time until passage ranged from 2.7 to 14.2 days. Nifedipine also increased expulsion rates for calculi with a mean diameter larger than 5 mm, ranging in size from 3.9 to 12.8 mm (RR=1.50; 95% CI, 1.34-1.68; NNT=4).4
Recommendations
The Joint European Association of Urology/ AUA Nephrolithiasis Guideline Panel recommends observation with periodic evaluation for patients newly diagnosed with ureteral calculi smaller than 10 mm.1 Patients may be offered medical expulsion therapy to facilitate calculus passage. Surveillance should be maintained until calculi pass; intervention should be considered if calculi don’t pass spontaneously within about 30 days.
The Panel states that patients with ureteral calculi larger than 10 mm could be observed (with or without medical expulsion therapy); however, most cases will require surgical intervention.1
Acknowledgements
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Medical Department of the United States Army or the US Army Service at large.
THE SIZE OF THE CALCULI, their location, and complicating factors such as infection should all be considered.
Most ureteral calculi smaller than 5 mm pass spontaneously, as do approximately half of calculi between 5 and 10 mm. Calculi larger than 10 mm are unlikely to pass without intervention. Distal calculi are more likely to pass spontaneously than calculi in mid- or proximal ureteral locations; most spontaneous passage occurs within 4 to 6 weeks (strength of recommendation [SOR]: A, prospective cohort studies).
All patients with calculi complicated by such factors as obstruction, infection, renal injury, or a single kidney require surgical consultation (SOR: C, expert opinion).
Medical expulsion therapy with alpha-blockers (usually tamsulosin) and nifedipine improves passage rates, including for some calculi larger than 10 mm (SOR: A, meta-analysis of prospective cohort studies).
Evidence summary
A meta-analysis of 5 prospective cohort studies evaluated the rate of spontaneous passage of ureteral calculi according to size. Calculi smaller than 5 mm passed spontaneously in 68% of patients (5 studies, N=224). Calculi between 5 and 10 mm passed spontaneously in 47% of patients (3 studies, N=104).1
A prospective cohort study evaluated spontaneous passage rates of ureteral calculi by size in 172 patients who were diagnosed by unenhanced helical computed tomography.2 Investigators found spontaneous passage rates of 87% for 1-mm calculi, 76% for 2- to 4-mm calculi, 60% for 5- to 7-mm calculi, 48% for 7- to 9-mm calculi, and 25% for calculi larger than 9 mm.
Spontaneous passage rates differed significantly for calculi 1 to 4 mm in size compared with calculi 5 to 7 mm in size (P<.001) and for calculi 5 to 7 mm in size compared with calculi 8 mm or larger (P<.001). Calculi in either the distal ureter or ureterovesicular junction were more likely to pass that those in the mid- or proximal ureter (75% to 79% vs 48% to 60%; P<.001).
Most smaller calculi pass in 4 to 6 weeks
Another prospective cohort study (N=75) found that most calculi pass spontaneously within 4 to 6 weeks. In 95% of patients, calculi passed within 31 days (2 mm or smaller), 40 days (2-4 mm), or 39 days (4-6 mm).3
Some cases require prompt surgery
The American Urological Association (AUA) expert panel recommends early surgical intervention, regardless of calculus size, under the following circumstances: obstruction with high-grade hydronephrosis, infection, impending renal deterioration, intractable pain, nausea and vomiting, or obstruction in a solitary or transplanted kidney.1
Medical expulsion therapy trumps waiting for distal calculi to pass
A meta-analysis comparing rates of calculus passage found that medical expulsion therapy was more effective than expectant management for patients with distal ureteral calculi. Sixteen RCTs (N=1235) evaluated alpha-antagonists (mostly tamsulosin), and 9 RCTs (N=686) evaluated nifedipine. Treat ment periods for medical expulsion therapy ranged from 30 to 60 days.
Alpha-antagonists increased expulsion rates over expectant management for calculi ranging in size from 3 to 18 mm with a mean diameter greater than 5 mm (relative risk [RR]=1.59; 95% confidence interval [CI], 1.44-1.75; number needed to treat [NNT]=3). The mean time until passage ranged from 2.7 to 14.2 days. Nifedipine also increased expulsion rates for calculi with a mean diameter larger than 5 mm, ranging in size from 3.9 to 12.8 mm (RR=1.50; 95% CI, 1.34-1.68; NNT=4).4
Recommendations
The Joint European Association of Urology/ AUA Nephrolithiasis Guideline Panel recommends observation with periodic evaluation for patients newly diagnosed with ureteral calculi smaller than 10 mm.1 Patients may be offered medical expulsion therapy to facilitate calculus passage. Surveillance should be maintained until calculi pass; intervention should be considered if calculi don’t pass spontaneously within about 30 days.
The Panel states that patients with ureteral calculi larger than 10 mm could be observed (with or without medical expulsion therapy); however, most cases will require surgical intervention.1
Acknowledgements
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Medical Department of the United States Army or the US Army Service at large.
1. European Association of Urology/American Urology Association Nephrolithiasis Guideline Panel. 2007 Guideline for the management of ureteral calculi. Available at: www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=uc. Accessed August 16, 2010.
2. Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to calculus size and location as revealed by unenhanced helical CT. Am J Roentgenol. 2002;178:101-103.
3. Miller OF, Kane CJ. Time to calculus passage for observed ureteral calculi: a guide for patient education. J Urol. 1999;162:688-691.
4. Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007;50:552-563.
1. European Association of Urology/American Urology Association Nephrolithiasis Guideline Panel. 2007 Guideline for the management of ureteral calculi. Available at: www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines.cfm?sub=uc. Accessed August 16, 2010.
2. Coll DM, Varanelli MJ, Smith RC. Relationship of spontaneous passage of ureteral calculi to calculus size and location as revealed by unenhanced helical CT. Am J Roentgenol. 2002;178:101-103.
3. Miller OF, Kane CJ. Time to calculus passage for observed ureteral calculi: a guide for patient education. J Urol. 1999;162:688-691.
4. Singh A, Alter HJ, Littlepage A. A systematic review of medical therapy to facilitate passage of ureteral calculi. Ann Emerg Med. 2007;50:552-563.
Evidence-based answers from the Family Physicians Inquiries Network