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Which complementary therapies can help patients with PMS?
CHASTEBERRY TREE AND CALCIUM have demonstrated efficacy and safety in treating symptoms of premenstrual syndrome (PMS) (strength of recommendation [SOR]: A, randomized controlled trials [RCTs]). Pyridoxine and saffron may be effective, but high doses of pyridoxine can cause neuropathy (SOR: B, RCT and meta-analysis of lower-quality studies).
Insufficient evidence exists to recommend magnesium. St. John’s wort and evening primrose oil aren’t effective for managing PMS (SOR: B, inconsistent or limited quality patient-oriented evidence). No evidence was found to support black cohosh or vitamin E.
Evidence summary
A double-blind RCT comparing chasteberry tree with placebo in 170 patients found a decrease in self-reported PMS symptom scores and an increase in response rate (defined as a 50% reduction in symptoms)—52% vs 24%—in the intervention group (number needed to treat [NNT]=3.5). Patients taking chasteberry tree had 1 occurrence of multiple abscesses and 1 of urticaria.1
A prospective, open-label study of chasteberry tree for PMS symptoms in 43 patients found a 42% decrease in self-assessed PMS symptom scores, with the greatest improvement in pain, behavior changes, negative feelings, and fluid retention. No serious adverse events occurred.2
A third study comparing chasteberry tree with fluoxetine in 19 patients found a decrease in premenstrual symptom scores for both fluoxetine (13 of 19 patients) and chasteberry tree (11 of 19 patients). No statistically significant differences were noted between the 2 groups. Chasteberry tree was well tolerated; most adverse effects occurred in patients receiving fluoxetine. The most frequent adverse effects with chasteberry tree were nausea in 5 patients and headache in 4.3
Symptoms decrease significantly after 3 calcium treatment cycles
Two RCTs (33 and 466 patients) comparing 1000 and 1200 mg of calcium with placebo found a significant decrease in PMS symptoms after 3 treatment cycles.4,5 Calcium improved negative affect, water retention, food cravings, and pain. In the first study, 73% of patients preferred taking calcium, compared with 15% who preferred placebo.
The second study found that, by the third treatment cycle, patients taking calcium had an overall 48% reduction in total symptom scores, compared with a 30% reduction in the control group. The most common adverse effects were headache, rhinitis, and nonspecific pain.
Watch out for neuropathy with high doses of pyridoxine
A meta-analysis of pyridoxine in doses from 50 to 600 mg per day for PMS included 9 RCTs. Relative to placebo, pyridoxine improved PMS symptom scores (odds ratio=2.32, 95% confidence interval, 1.95-2.54). The overall quality of studies was poor, however, with few subjects, widely varying doses, and different outcome measurements.6
Two subsequent RCTs of 40 and 96 patients that weren’t included in the meta-analysis failed to demonstrate reduced premenstrual symptoms.7,8 Long-term use of pyridoxine in doses >200 mg/d can cause neuropathy.
Saffron shows promise in small study
A recent double-blind RCT evaluated the effect of 2 cycles of treatment with saffron (Crocus sativus L), 30 mg twice daily, on PMS symptoms in 50 patients. Nineteen patients in the saffron group showed a response, defined as 50% reduction in symptom severity, compared with 2 patients in the placebo group (NNT=2). The study found no statistically significant difference in frequency of adverse effects.9
Evidence for magnesium is sparse
Two RCTs comparing magnesium with placebo had low precision because of small numbers and short treatment duration.10,11 The first (N=28) demonstrated reduced total Moos Menstrual Distress Questionnaire scores.10 The second study reported a decrease in fluid retention symptoms by 2 points on an 80-point scale (P<.009) at 2 months, but no difference in total score.11
A further study, begun as an open trial of magnesium infusion for premenstrual dysphoric disorder (N=6), found a dramatic reduction in mood symptom scores. After converting to a randomized, blinded design (N=10), no difference was found compared with placebo.12
St. John’s wort, evening primrose oil don’t work
One randomized, double-blind controlled trial (N=125) of 600 mg St. John’s wort vs placebo over 2 cycles of treatment found no significant changes in symptom score from baseline.13 Two double-blind crossover studies of 27 and 38 patients found that evening primrose oil had no effect on PMS symptoms.14,15
Recommendations
The Premenstrual Syndrome Guidelines of the American College of Obstetricians and Gynecologists (ACOG) state that calcium and magnesium have been shown to be effective in small trials and must be validated in larger trials before a strong evidence-based recommendation can be made. ACOG’s guidelines also report minimal effectiveness with vitamin B6 and vitamin E.16
1. Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study. BMJ. 2001;322:134-137.
2. Berger D, Schaffner W, Schrader E, et al. Efficacy of Vitex agnuscastus L extract Ze 440 in patients with premenstrual syndrome (PMS). Arch Gynecol Obstet. 2000;264:150-153.
3. Atmaca M, Kumru S, Tezcan E. Fluoxetine versus Vitex agnuscastus extract in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol. 2003;18:191-195.
4. Thys-Jacobs S, Ceccarelli S, Bierman A, et al. Calcium supplementation in premenstrual syndrome: a randomized crossover trial. J Gen Intern Med. 1989;4:183-189.
5. Thys-Jacobs S, Starkey P, Bernstein D, et al. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol. 1998;179:444-452.
6. Wyatt KM, Dimmock PW, Jones PW, et al. Efficacy of vitamin B6 in the treatment of premenstrual syndrome: systematic review. BMJ. 1999;318:1375-1381.
7. Diegoli MS, da Fonseca AM, Diegoli CA, et al. A double-blind trial of four medications to treat severe premenstrual syndrome. Int J Gynaecol Obstet. 1998;62:63-67.
8. Kashanian M, Mazinani R, Jalalmanesh S. Pyridoxine (vitamin B6) therapy for premenstrual syndrome. Int J Gynaecol Obstet. 2007;96:43-44.
9. Agha-Hosseini M, Kashani L, Aleyaseen A, et al. Crocus sativus L (saffron) in the treatment of premenstrual syndrome: a double-blind, randomised and placebo-controlled trial. BJOG. 2008;115:515-519.
10. Facchinetti F, Borella P, Sances G, et al. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol. 1991;78:177-181.
11. Walker AF, De Souza MC, Vickers MF, et al. Magnesium supplementation alleviates premenstrual symptoms of fluid retention. J Womens Health. 1998;7:1157-1165.
12. Khine K, Rosenstein DL, Elin RJ, et al. Magnesium (Mg) retention and mood effects after intravenous Mg infusion in premenstrual dysphoric disorder. Biol Psychiatry. 2006;59:327-333.
13. Hicks SM, Walker AF, Gallagher J, et al. The significance of “nonsignificance” in randomized controlled studies: a discussion inspired by a double-blinded study on St. John’s wort (Hypericum perforatum L.) for premenstrual symptoms. J Altern Complement Med. 2004;10:925-932.
14. Khoo SK, Munro C, Battistutta D. Evening primrose oil and treatment of premenstrual syndrome. Med J Aust. 1990;153:189-192.
15. Collins A, Cerin A, Coleman G, et al. Essential fatty acids in the treatment of premenstrual syndrome. Obstet Gynecol. 1993;81:93-98.
16. American College of Obstetricians and Gynecologists. Premenstrual Syndrome. ACOG Practice Bulletin No. 15. Washington, DC. April 2000.
CHASTEBERRY TREE AND CALCIUM have demonstrated efficacy and safety in treating symptoms of premenstrual syndrome (PMS) (strength of recommendation [SOR]: A, randomized controlled trials [RCTs]). Pyridoxine and saffron may be effective, but high doses of pyridoxine can cause neuropathy (SOR: B, RCT and meta-analysis of lower-quality studies).
Insufficient evidence exists to recommend magnesium. St. John’s wort and evening primrose oil aren’t effective for managing PMS (SOR: B, inconsistent or limited quality patient-oriented evidence). No evidence was found to support black cohosh or vitamin E.
Evidence summary
A double-blind RCT comparing chasteberry tree with placebo in 170 patients found a decrease in self-reported PMS symptom scores and an increase in response rate (defined as a 50% reduction in symptoms)—52% vs 24%—in the intervention group (number needed to treat [NNT]=3.5). Patients taking chasteberry tree had 1 occurrence of multiple abscesses and 1 of urticaria.1
A prospective, open-label study of chasteberry tree for PMS symptoms in 43 patients found a 42% decrease in self-assessed PMS symptom scores, with the greatest improvement in pain, behavior changes, negative feelings, and fluid retention. No serious adverse events occurred.2
A third study comparing chasteberry tree with fluoxetine in 19 patients found a decrease in premenstrual symptom scores for both fluoxetine (13 of 19 patients) and chasteberry tree (11 of 19 patients). No statistically significant differences were noted between the 2 groups. Chasteberry tree was well tolerated; most adverse effects occurred in patients receiving fluoxetine. The most frequent adverse effects with chasteberry tree were nausea in 5 patients and headache in 4.3
Symptoms decrease significantly after 3 calcium treatment cycles
Two RCTs (33 and 466 patients) comparing 1000 and 1200 mg of calcium with placebo found a significant decrease in PMS symptoms after 3 treatment cycles.4,5 Calcium improved negative affect, water retention, food cravings, and pain. In the first study, 73% of patients preferred taking calcium, compared with 15% who preferred placebo.
The second study found that, by the third treatment cycle, patients taking calcium had an overall 48% reduction in total symptom scores, compared with a 30% reduction in the control group. The most common adverse effects were headache, rhinitis, and nonspecific pain.
Watch out for neuropathy with high doses of pyridoxine
A meta-analysis of pyridoxine in doses from 50 to 600 mg per day for PMS included 9 RCTs. Relative to placebo, pyridoxine improved PMS symptom scores (odds ratio=2.32, 95% confidence interval, 1.95-2.54). The overall quality of studies was poor, however, with few subjects, widely varying doses, and different outcome measurements.6
Two subsequent RCTs of 40 and 96 patients that weren’t included in the meta-analysis failed to demonstrate reduced premenstrual symptoms.7,8 Long-term use of pyridoxine in doses >200 mg/d can cause neuropathy.
Saffron shows promise in small study
A recent double-blind RCT evaluated the effect of 2 cycles of treatment with saffron (Crocus sativus L), 30 mg twice daily, on PMS symptoms in 50 patients. Nineteen patients in the saffron group showed a response, defined as 50% reduction in symptom severity, compared with 2 patients in the placebo group (NNT=2). The study found no statistically significant difference in frequency of adverse effects.9
Evidence for magnesium is sparse
Two RCTs comparing magnesium with placebo had low precision because of small numbers and short treatment duration.10,11 The first (N=28) demonstrated reduced total Moos Menstrual Distress Questionnaire scores.10 The second study reported a decrease in fluid retention symptoms by 2 points on an 80-point scale (P<.009) at 2 months, but no difference in total score.11
A further study, begun as an open trial of magnesium infusion for premenstrual dysphoric disorder (N=6), found a dramatic reduction in mood symptom scores. After converting to a randomized, blinded design (N=10), no difference was found compared with placebo.12
St. John’s wort, evening primrose oil don’t work
One randomized, double-blind controlled trial (N=125) of 600 mg St. John’s wort vs placebo over 2 cycles of treatment found no significant changes in symptom score from baseline.13 Two double-blind crossover studies of 27 and 38 patients found that evening primrose oil had no effect on PMS symptoms.14,15
Recommendations
The Premenstrual Syndrome Guidelines of the American College of Obstetricians and Gynecologists (ACOG) state that calcium and magnesium have been shown to be effective in small trials and must be validated in larger trials before a strong evidence-based recommendation can be made. ACOG’s guidelines also report minimal effectiveness with vitamin B6 and vitamin E.16
CHASTEBERRY TREE AND CALCIUM have demonstrated efficacy and safety in treating symptoms of premenstrual syndrome (PMS) (strength of recommendation [SOR]: A, randomized controlled trials [RCTs]). Pyridoxine and saffron may be effective, but high doses of pyridoxine can cause neuropathy (SOR: B, RCT and meta-analysis of lower-quality studies).
Insufficient evidence exists to recommend magnesium. St. John’s wort and evening primrose oil aren’t effective for managing PMS (SOR: B, inconsistent or limited quality patient-oriented evidence). No evidence was found to support black cohosh or vitamin E.
Evidence summary
A double-blind RCT comparing chasteberry tree with placebo in 170 patients found a decrease in self-reported PMS symptom scores and an increase in response rate (defined as a 50% reduction in symptoms)—52% vs 24%—in the intervention group (number needed to treat [NNT]=3.5). Patients taking chasteberry tree had 1 occurrence of multiple abscesses and 1 of urticaria.1
A prospective, open-label study of chasteberry tree for PMS symptoms in 43 patients found a 42% decrease in self-assessed PMS symptom scores, with the greatest improvement in pain, behavior changes, negative feelings, and fluid retention. No serious adverse events occurred.2
A third study comparing chasteberry tree with fluoxetine in 19 patients found a decrease in premenstrual symptom scores for both fluoxetine (13 of 19 patients) and chasteberry tree (11 of 19 patients). No statistically significant differences were noted between the 2 groups. Chasteberry tree was well tolerated; most adverse effects occurred in patients receiving fluoxetine. The most frequent adverse effects with chasteberry tree were nausea in 5 patients and headache in 4.3
Symptoms decrease significantly after 3 calcium treatment cycles
Two RCTs (33 and 466 patients) comparing 1000 and 1200 mg of calcium with placebo found a significant decrease in PMS symptoms after 3 treatment cycles.4,5 Calcium improved negative affect, water retention, food cravings, and pain. In the first study, 73% of patients preferred taking calcium, compared with 15% who preferred placebo.
The second study found that, by the third treatment cycle, patients taking calcium had an overall 48% reduction in total symptom scores, compared with a 30% reduction in the control group. The most common adverse effects were headache, rhinitis, and nonspecific pain.
Watch out for neuropathy with high doses of pyridoxine
A meta-analysis of pyridoxine in doses from 50 to 600 mg per day for PMS included 9 RCTs. Relative to placebo, pyridoxine improved PMS symptom scores (odds ratio=2.32, 95% confidence interval, 1.95-2.54). The overall quality of studies was poor, however, with few subjects, widely varying doses, and different outcome measurements.6
Two subsequent RCTs of 40 and 96 patients that weren’t included in the meta-analysis failed to demonstrate reduced premenstrual symptoms.7,8 Long-term use of pyridoxine in doses >200 mg/d can cause neuropathy.
Saffron shows promise in small study
A recent double-blind RCT evaluated the effect of 2 cycles of treatment with saffron (Crocus sativus L), 30 mg twice daily, on PMS symptoms in 50 patients. Nineteen patients in the saffron group showed a response, defined as 50% reduction in symptom severity, compared with 2 patients in the placebo group (NNT=2). The study found no statistically significant difference in frequency of adverse effects.9
Evidence for magnesium is sparse
Two RCTs comparing magnesium with placebo had low precision because of small numbers and short treatment duration.10,11 The first (N=28) demonstrated reduced total Moos Menstrual Distress Questionnaire scores.10 The second study reported a decrease in fluid retention symptoms by 2 points on an 80-point scale (P<.009) at 2 months, but no difference in total score.11
A further study, begun as an open trial of magnesium infusion for premenstrual dysphoric disorder (N=6), found a dramatic reduction in mood symptom scores. After converting to a randomized, blinded design (N=10), no difference was found compared with placebo.12
St. John’s wort, evening primrose oil don’t work
One randomized, double-blind controlled trial (N=125) of 600 mg St. John’s wort vs placebo over 2 cycles of treatment found no significant changes in symptom score from baseline.13 Two double-blind crossover studies of 27 and 38 patients found that evening primrose oil had no effect on PMS symptoms.14,15
Recommendations
The Premenstrual Syndrome Guidelines of the American College of Obstetricians and Gynecologists (ACOG) state that calcium and magnesium have been shown to be effective in small trials and must be validated in larger trials before a strong evidence-based recommendation can be made. ACOG’s guidelines also report minimal effectiveness with vitamin B6 and vitamin E.16
1. Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study. BMJ. 2001;322:134-137.
2. Berger D, Schaffner W, Schrader E, et al. Efficacy of Vitex agnuscastus L extract Ze 440 in patients with premenstrual syndrome (PMS). Arch Gynecol Obstet. 2000;264:150-153.
3. Atmaca M, Kumru S, Tezcan E. Fluoxetine versus Vitex agnuscastus extract in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol. 2003;18:191-195.
4. Thys-Jacobs S, Ceccarelli S, Bierman A, et al. Calcium supplementation in premenstrual syndrome: a randomized crossover trial. J Gen Intern Med. 1989;4:183-189.
5. Thys-Jacobs S, Starkey P, Bernstein D, et al. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol. 1998;179:444-452.
6. Wyatt KM, Dimmock PW, Jones PW, et al. Efficacy of vitamin B6 in the treatment of premenstrual syndrome: systematic review. BMJ. 1999;318:1375-1381.
7. Diegoli MS, da Fonseca AM, Diegoli CA, et al. A double-blind trial of four medications to treat severe premenstrual syndrome. Int J Gynaecol Obstet. 1998;62:63-67.
8. Kashanian M, Mazinani R, Jalalmanesh S. Pyridoxine (vitamin B6) therapy for premenstrual syndrome. Int J Gynaecol Obstet. 2007;96:43-44.
9. Agha-Hosseini M, Kashani L, Aleyaseen A, et al. Crocus sativus L (saffron) in the treatment of premenstrual syndrome: a double-blind, randomised and placebo-controlled trial. BJOG. 2008;115:515-519.
10. Facchinetti F, Borella P, Sances G, et al. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol. 1991;78:177-181.
11. Walker AF, De Souza MC, Vickers MF, et al. Magnesium supplementation alleviates premenstrual symptoms of fluid retention. J Womens Health. 1998;7:1157-1165.
12. Khine K, Rosenstein DL, Elin RJ, et al. Magnesium (Mg) retention and mood effects after intravenous Mg infusion in premenstrual dysphoric disorder. Biol Psychiatry. 2006;59:327-333.
13. Hicks SM, Walker AF, Gallagher J, et al. The significance of “nonsignificance” in randomized controlled studies: a discussion inspired by a double-blinded study on St. John’s wort (Hypericum perforatum L.) for premenstrual symptoms. J Altern Complement Med. 2004;10:925-932.
14. Khoo SK, Munro C, Battistutta D. Evening primrose oil and treatment of premenstrual syndrome. Med J Aust. 1990;153:189-192.
15. Collins A, Cerin A, Coleman G, et al. Essential fatty acids in the treatment of premenstrual syndrome. Obstet Gynecol. 1993;81:93-98.
16. American College of Obstetricians and Gynecologists. Premenstrual Syndrome. ACOG Practice Bulletin No. 15. Washington, DC. April 2000.
1. Schellenberg R. Treatment for the premenstrual syndrome with agnus castus fruit extract: prospective, randomised, placebo controlled study. BMJ. 2001;322:134-137.
2. Berger D, Schaffner W, Schrader E, et al. Efficacy of Vitex agnuscastus L extract Ze 440 in patients with premenstrual syndrome (PMS). Arch Gynecol Obstet. 2000;264:150-153.
3. Atmaca M, Kumru S, Tezcan E. Fluoxetine versus Vitex agnuscastus extract in the treatment of premenstrual dysphoric disorder. Hum Psychopharmacol. 2003;18:191-195.
4. Thys-Jacobs S, Ceccarelli S, Bierman A, et al. Calcium supplementation in premenstrual syndrome: a randomized crossover trial. J Gen Intern Med. 1989;4:183-189.
5. Thys-Jacobs S, Starkey P, Bernstein D, et al. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol. 1998;179:444-452.
6. Wyatt KM, Dimmock PW, Jones PW, et al. Efficacy of vitamin B6 in the treatment of premenstrual syndrome: systematic review. BMJ. 1999;318:1375-1381.
7. Diegoli MS, da Fonseca AM, Diegoli CA, et al. A double-blind trial of four medications to treat severe premenstrual syndrome. Int J Gynaecol Obstet. 1998;62:63-67.
8. Kashanian M, Mazinani R, Jalalmanesh S. Pyridoxine (vitamin B6) therapy for premenstrual syndrome. Int J Gynaecol Obstet. 2007;96:43-44.
9. Agha-Hosseini M, Kashani L, Aleyaseen A, et al. Crocus sativus L (saffron) in the treatment of premenstrual syndrome: a double-blind, randomised and placebo-controlled trial. BJOG. 2008;115:515-519.
10. Facchinetti F, Borella P, Sances G, et al. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol. 1991;78:177-181.
11. Walker AF, De Souza MC, Vickers MF, et al. Magnesium supplementation alleviates premenstrual symptoms of fluid retention. J Womens Health. 1998;7:1157-1165.
12. Khine K, Rosenstein DL, Elin RJ, et al. Magnesium (Mg) retention and mood effects after intravenous Mg infusion in premenstrual dysphoric disorder. Biol Psychiatry. 2006;59:327-333.
13. Hicks SM, Walker AF, Gallagher J, et al. The significance of “nonsignificance” in randomized controlled studies: a discussion inspired by a double-blinded study on St. John’s wort (Hypericum perforatum L.) for premenstrual symptoms. J Altern Complement Med. 2004;10:925-932.
14. Khoo SK, Munro C, Battistutta D. Evening primrose oil and treatment of premenstrual syndrome. Med J Aust. 1990;153:189-192.
15. Collins A, Cerin A, Coleman G, et al. Essential fatty acids in the treatment of premenstrual syndrome. Obstet Gynecol. 1993;81:93-98.
16. American College of Obstetricians and Gynecologists. Premenstrual Syndrome. ACOG Practice Bulletin No. 15. Washington, DC. April 2000.
Evidence-based answers from the Family Physicians Inquiries Network
What is the preferred treatment for a child with mild persistent asthma?
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
Low-dose inhaled corticosteroids are the preferred treatment for children with mild persistent asthma because they demonstrate superior reduction in severity and frequency of asthma exacerbations compared with alternatives (strength of recommendation [SOR]: A, based on multiple randomized controlled trials). As add-on therapy, nedocromil, theophylline, and cromolyn have all demonstrated a modest benefit in symptom control; leukotriene receptor antagonists are also recommended based on data from older children (SOR: B, cohort study). Unlike treatment of moderate or severe asthma, long-acting beta-agonists are not recommended (SOR: A, randomized trials).
Clear medication choices for mild asthma are supported by good evidence
John Heintzman, MD
Oregon Health and Science University, Portland
Physicians who routinely treat children with asthma are fortunate to have the body of evidence outlined in this review. Clear medication choices are supported in most instances by relatively clear comparisons with alternatives. In my practice, where many children can be classified in the “mild persistent” category, I am always surprised at how many patients’ families lack a clear understanding of the factors that trigger a child’s asthma and how to avoid them.
Another common clinical scenario among children and adolescents is exercise-induced asthma. Depending on the sport, the asthma can be classified as “mild persistent” or “mild intermittent.” for true intermittent symptoms, my clinical experience (and often parental preference) argues for pre-activity treatment with short acting beta-agonists as the most practical therapy.
Evidence summary
Mild persistent asthma is defined as forced expiratory volume over 1 second (FEV1) ≥80% predicted, with daytime symptoms more than twice per week but less than once daily, and nighttime symptoms more often than twice monthly.1
Low-dose inhaled corticosteroids
Two large randomized trials support using low-dose inhaled corticosteroids in these children. The Childhood Asthma Management Program (CAMP) study, which included 1041 children, evaluated treatment with either budesonide or nedocromil vs placebo. Patients taking budesonide had a lower rate of urgent care visits (absolute risk reduction [ARR]=10%; number needed to treat [NNT]=10; P=.02) compared with children taking nedocromil (ARR=6%; NNT=17; P=.02). The urgent care visits were reported as number of visits per 100 person-years.
In practical terms, this means that in order to decrease 1 urgent care visit, 1 patient would need to take budesonide for 10 years. However, because rates are not necessarily homogenous over time, the number of visits decreased during the first year may be different than the number of events decreased throughout the tenth year.
Children taking budesonide experienced 21.5% more episode-free days than those taking placebo (P=.01). No change was observed in the nedocromil group.2 In the inhaled Steroid Treatment As Regular Therapy (START) in early asthma study, budesonide demonstrated a 44% relative reduction in time to first severe asthma related event, compared with placebo (95% confidence interval [CI], 0.45–0.71; NNT=44; P=.0001).3
Theophylline
Theophylline is considered an alternative to inhaled corticosteroids. One study compared beclomethasone with theophylline in 195 children. This study found near-equivalent efficacy in doctor visits, hospitalizations, monthly peak expiratory flow rates, and FEV1; however, beclomethasone was superior to theophylline in maintaining symptom control and decreasing the use of inhaled bronchodilators and systemic steroids.
When compared with beclomethasone, theophylline was linked to 14% more central nervous system adverse effects (P<.001) and 17% more gastrointestinal disturbances (P<.001). Although beclomethasone induced more oral candidiasis compared with theophylline (8.9% vs 2.4%; P<.001), the incidence of this infection can be reduced by using a spacer.
Long-term systemic effects
The potential long-term adverse systemic effects of inhaled corticosteroids on growth, bone metabolism, and pituitary-adrenal function call for longer-term studies.4 A systematic review of 15 trials reported that the protective effect of leukotriene receptor antagonists is inferior to inhaled corticosteroids for adults (relative risk [RR]=1.71; 95% CI, 1.40–2.09); however, evidence is insufficient to extrapolate this to children.5
Beta-agonists
Evidence does not support use of long-acting beta-agonists as monotherapy or in combination with other medications for children with mild persistent asthma. Although 1 study showed an improvement in lung function for children taking budesonide plus formoterol compared with budesonide alone, the rate of severe exacerbations was lower for those taking budesonide alone (62% decrease vs 55.8% decrease; P=.001). Both groups had a 32% decrease in the number of rescue inhalations per day when compared with placebo (P=.0008).6
Recommendations from others
Recommendations are listed in the TABLE.1,7,8 Unlike the NAEPP and GINA asthma guidelines, the BTS/SIGN asthma guidelines define no objective measurement or staging classification to diagnose asthma among children. Diagnosis is determined by a child’s response to medication.8 Independent of any daily controller medication use, all children should have a short acting bronchodilator on hand in case of an acute attack.1,8
TABLE
Recommendations for treating mild persistent asthma
| GUIDELINE | DAILY CONTROLLER MEDICATION | ALTERNATIVE TREATMENT |
|---|---|---|
| National Asthma Education and Prevention Program (NAEPP)1 | Low-dose inhaled corticosteroids | Children <5: cromolyn, LTRAs Children >5: cromolyn, LTRAs, nedocromil, sustained release theophylline |
| Global initiative for asthma (GINA)7 | low-dose inhaled corticosteroids | All children: sustained released theophylline, Cromone, LTRAs |
| British Thoracic Society/Scottish intercollegiate Guidelines network (BTS/SIGN)8 | Inhaled steroids | All children: LTRAs, theophylline Children >5: cromones, nedocromil |
| LRTA leukotriene receptor antagonists. | ||
| Sources: NAEPP J Allergy Clin Immunol 20021; GINA Guidelines and Resources 20057 and BTS/SIGN, Thorax 2003.8 | ||
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
1. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics—2002. National Asthma Education and Prevention Program. J Allergy Clin Immunol 2002;110:S141-S219.
2. Long-term effects of budesonide or nedocromil in children with asthma. The Childhood Asthma Management Program Research Group. N Engl J Med 2000;343:1054-1063.
3. Pauwels RA, Pedersen S, Busse WW, et al. START Investigators Group. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003;361:1071-1076.
4. Reed CE, Offord KP, Nelson HS, Li JT, Tinkelman DG. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998;101:14-23.
5. Ducharme FM, Salvio F, Ducharme F. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review). In: The Cochrane Library. 2006 Issue 2. Chichester, UK: John Wiley and Sons, Ltd.
6. O’byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001;164:1392-1397.
7. The Global Initiative for Asthma. Guidelines and Resources: 2005 Update. Available at: www.ginasthma.com/Guidelineitem.asp??I1=2&I2=1&intId=60. Accessed January 9, 2007.
8. British Thoracic Society Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. A national clinical guideline. Thorax 2003;58:i1-i94.
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