Thomas W. Marsland, MD

ABSTRACT

BACKGROUND: Acute cough and bronchitis are common primary care diagnoses often treated withβ₂-agonists (eg, albuterol). This systematic review sought to assess whether β₂-agonists constitute effective treatment for these conditions.

POPULATION STUDIED: A total of 492 patients older than 2 years was gathered from randomized controlled trials measuring the efficacy of β₂-agonists versus placebo or erythromycin for treatment of “acute cough,” “acute bronchitis,” or “acute transient cough” without clear etiology (pneumonia, pertussis, or sinusitis). The maximum mean duration of cough acceptable for inclusion was 30 days. Although no information was provided about specific diagnostic criteria, numbers of adult smokers and wheezers, or specifics of clinical presentation (fever, tachypnea), the population studied seems similar to that of a typical family practice.

STUDY DESIGN AND VALIDITY: The authors searched multiple databases, including MEDLINE and EMBASE, The Cochrane Library, reference lists of retrieved articles, review articles, textbooks, and information from manufacturers. Two investigators examined the search results, forwarding those that met inclusion criteria to the remaining 3 investigators, who graded the studies using the Jadad methodology scale, on the basis of randomization, blinding, and withdrawals. Disagreement regarding study quality was common (κ= 0.27) and was resolved by discussion. Included studies were then divided into 3 groups for analysis: 2 pediatric trials comparing β₂-agonists with placebo; 4 adult trials comparing β₂-agonists with placebo; and 1 adult trial comparing β₂-agonists with erythromycin. Summary statistics were generated using Review Manager 4.1.

OUTCOMES MEASURED: Outcomes measured included cough severity, duration, and productivity; lost work days; night cough; and adverse effects. Only one trial measured compliance. Cost and patient satisfaction were not addressed.

RESULTS: The overall quality of the included studies was fair. The pediatric studies revealed no benefit from albuterol. In the adult placebo trials, 1 demonstrated no benefit and 3 demonstrated slight improvement in cough severity. In the erythromycin study, those in the albuterol group had less cough or productive cough after 7 days, but the groups did not differ in night cough, time to improvement, or missed work days. When all the adult studies were combined, there was no difference in cough after 7 days, in productive cough, or in night cough. Studies that had enrolled more wheezing patients were more likely to show benefits than those that had not.

ABSTRACT

BACKGROUND: Acute cough and bronchitis are common primary care diagnoses often treated withβ₂-agonists (eg, albuterol). This systematic review sought to assess whether β₂-agonists constitute effective treatment for these conditions.

POPULATION STUDIED: A total of 492 patients older than 2 years was gathered from randomized controlled trials measuring the efficacy of β₂-agonists versus placebo or erythromycin for treatment of “acute cough,” “acute bronchitis,” or “acute transient cough” without clear etiology (pneumonia, pertussis, or sinusitis). The maximum mean duration of cough acceptable for inclusion was 30 days. Although no information was provided about specific diagnostic criteria, numbers of adult smokers and wheezers, or specifics of clinical presentation (fever, tachypnea), the population studied seems similar to that of a typical family practice.

STUDY DESIGN AND VALIDITY: The authors searched multiple databases, including MEDLINE and EMBASE, The Cochrane Library, reference lists of retrieved articles, review articles, textbooks, and information from manufacturers. Two investigators examined the search results, forwarding those that met inclusion criteria to the remaining 3 investigators, who graded the studies using the Jadad methodology scale, on the basis of randomization, blinding, and withdrawals. Disagreement regarding study quality was common (κ= 0.27) and was resolved by discussion. Included studies were then divided into 3 groups for analysis: 2 pediatric trials comparing β₂-agonists with placebo; 4 adult trials comparing β₂-agonists with placebo; and 1 adult trial comparing β₂-agonists with erythromycin. Summary statistics were generated using Review Manager 4.1.

OUTCOMES MEASURED: Outcomes measured included cough severity, duration, and productivity; lost work days; night cough; and adverse effects. Only one trial measured compliance. Cost and patient satisfaction were not addressed.

RESULTS: The overall quality of the included studies was fair. The pediatric studies revealed no benefit from albuterol. In the adult placebo trials, 1 demonstrated no benefit and 3 demonstrated slight improvement in cough severity. In the erythromycin study, those in the albuterol group had less cough or productive cough after 7 days, but the groups did not differ in night cough, time to improvement, or missed work days. When all the adult studies were combined, there was no difference in cough after 7 days, in productive cough, or in night cough. Studies that had enrolled more wheezing patients were more likely to show benefits than those that had not.

ABSTRACT

BACKGROUND: Acute cough and bronchitis are common primary care diagnoses often treated withβ₂-agonists (eg, albuterol). This systematic review sought to assess whether β₂-agonists constitute effective treatment for these conditions.

POPULATION STUDIED: A total of 492 patients older than 2 years was gathered from randomized controlled trials measuring the efficacy of β₂-agonists versus placebo or erythromycin for treatment of “acute cough,” “acute bronchitis,” or “acute transient cough” without clear etiology (pneumonia, pertussis, or sinusitis). The maximum mean duration of cough acceptable for inclusion was 30 days. Although no information was provided about specific diagnostic criteria, numbers of adult smokers and wheezers, or specifics of clinical presentation (fever, tachypnea), the population studied seems similar to that of a typical family practice.

STUDY DESIGN AND VALIDITY: The authors searched multiple databases, including MEDLINE and EMBASE, The Cochrane Library, reference lists of retrieved articles, review articles, textbooks, and information from manufacturers. Two investigators examined the search results, forwarding those that met inclusion criteria to the remaining 3 investigators, who graded the studies using the Jadad methodology scale, on the basis of randomization, blinding, and withdrawals. Disagreement regarding study quality was common (κ= 0.27) and was resolved by discussion. Included studies were then divided into 3 groups for analysis: 2 pediatric trials comparing β₂-agonists with placebo; 4 adult trials comparing β₂-agonists with placebo; and 1 adult trial comparing β₂-agonists with erythromycin. Summary statistics were generated using Review Manager 4.1.

OUTCOMES MEASURED: Outcomes measured included cough severity, duration, and productivity; lost work days; night cough; and adverse effects. Only one trial measured compliance. Cost and patient satisfaction were not addressed.

RESULTS: The overall quality of the included studies was fair. The pediatric studies revealed no benefit from albuterol. In the adult placebo trials, 1 demonstrated no benefit and 3 demonstrated slight improvement in cough severity. In the erythromycin study, those in the albuterol group had less cough or productive cough after 7 days, but the groups did not differ in night cough, time to improvement, or missed work days. When all the adult studies were combined, there was no difference in cough after 7 days, in productive cough, or in night cough. Studies that had enrolled more wheezing patients were more likely to show benefits than those that had not.

BACKGROUND: There is concern about the effect of antihistamines in children on alertness and school performance. This study assessed the impact of first- and second-generation antihistamines on school performance.

POPULATION STUDIED: The investigators enrolled 63 children aged 8 to 10 years with antihistamine-treated allergic rhinitis but no current symptoms. Subjects underwent skin testing to prove they were allergic to allergens not currently in season. They had no known learning disabilities or illnesses that might have an impact on the study. In general, the subjects seem similar to patients family physicians see, although no information about the study group composition by weight, sex, ethnicity, specific allergy history, or other medical history was given.

STUDY DESIGN AND VALIDITY: This was a double-blind placebo-controlled study. Participants were randomized to 1 of 3 treatment groups: diphenhdramine (Benadryl, dye-free) 25 mg twice daily, loratadine (Claritin) 10 mg in the morning with placebo in the evening, or placebo twice daily. To simulate an everyday classroom experience, an existing laboratory school was used on 3 consecutive weekends. The medications were administered on study days 1, 2, and 8 at 7:45 AM and 1:45 PM. The subjects were given 1-hour lectures and 1-hour reading assignments on plant biology. After 90 to 120 minutes, they completed computerized testing to assess retention and reaction times. Covariate analysis was performed, with adjustments for sex, age, baseline reading ability, and weight, along with correction for multiple comparisons. The methodology of this study was strong. The major strengths were the randomized design, the use of patients with known allergies, and the realistic laboratory school setting with appropriate and innovative “blinded” testing. The major weaknesses of the study were the relatively small sample size, and—despite the commendable efforts of the investigators—the inherent artificiality of a weekend school that takes place only over a few weekends. Other minor limitations include the short duration of the study and the lack of assessment of baseline medical history. Interpretation was hampered by the lack of information regarding the results of randomization.

OUTCOME MEASURED: Outcomes measured by computer assessment were: (1) retention of material presented orally (average number of errors in 25 questions about teacher presentations); (2) retention of materials presented in a written format (average number of errors in 25 questions from the readings); (3) reaction time for answers (average for all correct computer test questions); and (4) child self report of somnolence.

RESULTS: At the end of the trial, there were no significant differences noted in the verbal instruction score, reading test score, reaction time, or somnolence scale among students in the 3 treatment groups. Female subjects tended to rate somnolence slightly higher than male subjects did; heavier subjects rated somnolence lower.

BACKGROUND: There is concern about the effect of antihistamines in children on alertness and school performance. This study assessed the impact of first- and second-generation antihistamines on school performance.

POPULATION STUDIED: The investigators enrolled 63 children aged 8 to 10 years with antihistamine-treated allergic rhinitis but no current symptoms. Subjects underwent skin testing to prove they were allergic to allergens not currently in season. They had no known learning disabilities or illnesses that might have an impact on the study. In general, the subjects seem similar to patients family physicians see, although no information about the study group composition by weight, sex, ethnicity, specific allergy history, or other medical history was given.

STUDY DESIGN AND VALIDITY: This was a double-blind placebo-controlled study. Participants were randomized to 1 of 3 treatment groups: diphenhdramine (Benadryl, dye-free) 25 mg twice daily, loratadine (Claritin) 10 mg in the morning with placebo in the evening, or placebo twice daily. To simulate an everyday classroom experience, an existing laboratory school was used on 3 consecutive weekends. The medications were administered on study days 1, 2, and 8 at 7:45 AM and 1:45 PM. The subjects were given 1-hour lectures and 1-hour reading assignments on plant biology. After 90 to 120 minutes, they completed computerized testing to assess retention and reaction times. Covariate analysis was performed, with adjustments for sex, age, baseline reading ability, and weight, along with correction for multiple comparisons. The methodology of this study was strong. The major strengths were the randomized design, the use of patients with known allergies, and the realistic laboratory school setting with appropriate and innovative “blinded” testing. The major weaknesses of the study were the relatively small sample size, and—despite the commendable efforts of the investigators—the inherent artificiality of a weekend school that takes place only over a few weekends. Other minor limitations include the short duration of the study and the lack of assessment of baseline medical history. Interpretation was hampered by the lack of information regarding the results of randomization.

OUTCOME MEASURED: Outcomes measured by computer assessment were: (1) retention of material presented orally (average number of errors in 25 questions about teacher presentations); (2) retention of materials presented in a written format (average number of errors in 25 questions from the readings); (3) reaction time for answers (average for all correct computer test questions); and (4) child self report of somnolence.

RESULTS: At the end of the trial, there were no significant differences noted in the verbal instruction score, reading test score, reaction time, or somnolence scale among students in the 3 treatment groups. Female subjects tended to rate somnolence slightly higher than male subjects did; heavier subjects rated somnolence lower.

BACKGROUND: There is concern about the effect of antihistamines in children on alertness and school performance. This study assessed the impact of first- and second-generation antihistamines on school performance.

POPULATION STUDIED: The investigators enrolled 63 children aged 8 to 10 years with antihistamine-treated allergic rhinitis but no current symptoms. Subjects underwent skin testing to prove they were allergic to allergens not currently in season. They had no known learning disabilities or illnesses that might have an impact on the study. In general, the subjects seem similar to patients family physicians see, although no information about the study group composition by weight, sex, ethnicity, specific allergy history, or other medical history was given.

STUDY DESIGN AND VALIDITY: This was a double-blind placebo-controlled study. Participants were randomized to 1 of 3 treatment groups: diphenhdramine (Benadryl, dye-free) 25 mg twice daily, loratadine (Claritin) 10 mg in the morning with placebo in the evening, or placebo twice daily. To simulate an everyday classroom experience, an existing laboratory school was used on 3 consecutive weekends. The medications were administered on study days 1, 2, and 8 at 7:45 AM and 1:45 PM. The subjects were given 1-hour lectures and 1-hour reading assignments on plant biology. After 90 to 120 minutes, they completed computerized testing to assess retention and reaction times. Covariate analysis was performed, with adjustments for sex, age, baseline reading ability, and weight, along with correction for multiple comparisons. The methodology of this study was strong. The major strengths were the randomized design, the use of patients with known allergies, and the realistic laboratory school setting with appropriate and innovative “blinded” testing. The major weaknesses of the study were the relatively small sample size, and—despite the commendable efforts of the investigators—the inherent artificiality of a weekend school that takes place only over a few weekends. Other minor limitations include the short duration of the study and the lack of assessment of baseline medical history. Interpretation was hampered by the lack of information regarding the results of randomization.

OUTCOME MEASURED: Outcomes measured by computer assessment were: (1) retention of material presented orally (average number of errors in 25 questions about teacher presentations); (2) retention of materials presented in a written format (average number of errors in 25 questions from the readings); (3) reaction time for answers (average for all correct computer test questions); and (4) child self report of somnolence.

RESULTS: At the end of the trial, there were no significant differences noted in the verbal instruction score, reading test score, reaction time, or somnolence scale among students in the 3 treatment groups. Female subjects tended to rate somnolence slightly higher than male subjects did; heavier subjects rated somnolence lower.

BACKGROUND: Depression is common in primary care, but little is known about gender differences in response to medication. This randomized trial compared men and women in response to selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

POPULATION STUDIED: A total of 235 men and 400 women between 21 and 65 years who meet Diagnostic and Statistical Manual of Mental Disorders, third edition, revised criteria for major depression with or without dysthymia were enrolled at 12 centers. The average age for men and women was 43 and 40 years, respectively. Of these, 91% were white; 64% had recurrent depression; 54% were also dysthymic; and 57% were previously treated with pharmacotherapy. Depressive symptoms were severe, averaging 25 on the Hamilton Depression (HAM-D) scale. The study population was probably similar to many patients seen by family physicians but with more severe depressive symptoms and more dysthymia. Caution should be exercised in extrapolating results to patients with mild depression, patients of color, or anyone older than 65 years.

STUDY DESIGN AND VALIDITY: This was a randomized controlled trial (allocation assignment concealed). Subjects were given imipramine or sertraline starting at 50 mg per day. Doses were increased until therapeutic results or intolerable side effects occurred, to an average of approximately 140 mg per day of sertraline and 200 mg per day for imipramine. Response to medication was measured by the HAM-D, Beck, and Clinical Global Severity and Improvement (CGI) scales. Analyses of baseline characteristics and end points were performed using the Mantel-Haenszel chi-square and analysis of variance, adjusted for site, baseline severity, and type of depression. Methodologic strengths include the randomized design, efforts to conceal allocation, and use of both intention-to-treat and efficacy-only analysis. Minor weaknesses included lack of information about treatment groups at baseline, absence of a true placebo, and the lack of control for potentially important confounding factors, such as concurrent psychotherapy, other treatments, and social support.

OUTCOMES MEASURED: Response was defined as a 50% decrease of HAM-D score, a HAM-D score of less than 15, a CGI severity score of less than or equal to 3, or a CGI improvement score of 1 or 2. Compliance, side effects, and withdrawals were also tracked. Outcomes important in primary care that were not addressed include other clinical outcomes (suicide attempts, hospitalization), the use of other modalities (additional medication, electroconvulsive therapy, therapy), functional status, patient satisfaction, and cost of care.

RESULTS: Men and women were somewhat different at baseline, although the authors did not report the characteristics of each treatment subgroup. Women were significantly more likely to have been treated for depression and to have a first-degree relative with depression, while men were more likely to be married and to have coexistent dysthymia. Follow-up was complete. Women responded better to sertraline than imipramine (57% improved vs 46%; P=.03; number needed to treat [NNT]=8), and men responded more to imipramine than to sertraline (62% vs 45%; P=.03; NNT=6). Women taking imipramine were more likely to withdraw from the study than those taking sertraline (26% vs 14%; P=.02; NNH=10), but women completing a course of imipramine still had a significantly poorer response than those taking sertraline. Men and women taking either drug showed no significant sex differences in overall frequency of treatment-emergent adverse events; however, more than 90% of all patients reported adverse effects, and adverse effects were the most common reason for withdrawal from the study. For men, imipramine caused significantly more dry mouth, dizziness, and constipation than sertralin, and a similarly high rate of sexual dysfunction and somnolence. For women, sertraline caused significantly more insomnia and diarrhea and less constipation and dry mouth than imipramine.

BACKGROUND: Depression is common in primary care, but little is known about gender differences in response to medication. This randomized trial compared men and women in response to selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

POPULATION STUDIED: A total of 235 men and 400 women between 21 and 65 years who meet Diagnostic and Statistical Manual of Mental Disorders, third edition, revised criteria for major depression with or without dysthymia were enrolled at 12 centers. The average age for men and women was 43 and 40 years, respectively. Of these, 91% were white; 64% had recurrent depression; 54% were also dysthymic; and 57% were previously treated with pharmacotherapy. Depressive symptoms were severe, averaging 25 on the Hamilton Depression (HAM-D) scale. The study population was probably similar to many patients seen by family physicians but with more severe depressive symptoms and more dysthymia. Caution should be exercised in extrapolating results to patients with mild depression, patients of color, or anyone older than 65 years.

STUDY DESIGN AND VALIDITY: This was a randomized controlled trial (allocation assignment concealed). Subjects were given imipramine or sertraline starting at 50 mg per day. Doses were increased until therapeutic results or intolerable side effects occurred, to an average of approximately 140 mg per day of sertraline and 200 mg per day for imipramine. Response to medication was measured by the HAM-D, Beck, and Clinical Global Severity and Improvement (CGI) scales. Analyses of baseline characteristics and end points were performed using the Mantel-Haenszel chi-square and analysis of variance, adjusted for site, baseline severity, and type of depression. Methodologic strengths include the randomized design, efforts to conceal allocation, and use of both intention-to-treat and efficacy-only analysis. Minor weaknesses included lack of information about treatment groups at baseline, absence of a true placebo, and the lack of control for potentially important confounding factors, such as concurrent psychotherapy, other treatments, and social support.

OUTCOMES MEASURED: Response was defined as a 50% decrease of HAM-D score, a HAM-D score of less than 15, a CGI severity score of less than or equal to 3, or a CGI improvement score of 1 or 2. Compliance, side effects, and withdrawals were also tracked. Outcomes important in primary care that were not addressed include other clinical outcomes (suicide attempts, hospitalization), the use of other modalities (additional medication, electroconvulsive therapy, therapy), functional status, patient satisfaction, and cost of care.

RESULTS: Men and women were somewhat different at baseline, although the authors did not report the characteristics of each treatment subgroup. Women were significantly more likely to have been treated for depression and to have a first-degree relative with depression, while men were more likely to be married and to have coexistent dysthymia. Follow-up was complete. Women responded better to sertraline than imipramine (57% improved vs 46%; P=.03; number needed to treat [NNT]=8), and men responded more to imipramine than to sertraline (62% vs 45%; P=.03; NNT=6). Women taking imipramine were more likely to withdraw from the study than those taking sertraline (26% vs 14%; P=.02; NNH=10), but women completing a course of imipramine still had a significantly poorer response than those taking sertraline. Men and women taking either drug showed no significant sex differences in overall frequency of treatment-emergent adverse events; however, more than 90% of all patients reported adverse effects, and adverse effects were the most common reason for withdrawal from the study. For men, imipramine caused significantly more dry mouth, dizziness, and constipation than sertralin, and a similarly high rate of sexual dysfunction and somnolence. For women, sertraline caused significantly more insomnia and diarrhea and less constipation and dry mouth than imipramine.

BACKGROUND: Depression is common in primary care, but little is known about gender differences in response to medication. This randomized trial compared men and women in response to selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).

POPULATION STUDIED: A total of 235 men and 400 women between 21 and 65 years who meet Diagnostic and Statistical Manual of Mental Disorders, third edition, revised criteria for major depression with or without dysthymia were enrolled at 12 centers. The average age for men and women was 43 and 40 years, respectively. Of these, 91% were white; 64% had recurrent depression; 54% were also dysthymic; and 57% were previously treated with pharmacotherapy. Depressive symptoms were severe, averaging 25 on the Hamilton Depression (HAM-D) scale. The study population was probably similar to many patients seen by family physicians but with more severe depressive symptoms and more dysthymia. Caution should be exercised in extrapolating results to patients with mild depression, patients of color, or anyone older than 65 years.

STUDY DESIGN AND VALIDITY: This was a randomized controlled trial (allocation assignment concealed). Subjects were given imipramine or sertraline starting at 50 mg per day. Doses were increased until therapeutic results or intolerable side effects occurred, to an average of approximately 140 mg per day of sertraline and 200 mg per day for imipramine. Response to medication was measured by the HAM-D, Beck, and Clinical Global Severity and Improvement (CGI) scales. Analyses of baseline characteristics and end points were performed using the Mantel-Haenszel chi-square and analysis of variance, adjusted for site, baseline severity, and type of depression. Methodologic strengths include the randomized design, efforts to conceal allocation, and use of both intention-to-treat and efficacy-only analysis. Minor weaknesses included lack of information about treatment groups at baseline, absence of a true placebo, and the lack of control for potentially important confounding factors, such as concurrent psychotherapy, other treatments, and social support.

OUTCOMES MEASURED: Response was defined as a 50% decrease of HAM-D score, a HAM-D score of less than 15, a CGI severity score of less than or equal to 3, or a CGI improvement score of 1 or 2. Compliance, side effects, and withdrawals were also tracked. Outcomes important in primary care that were not addressed include other clinical outcomes (suicide attempts, hospitalization), the use of other modalities (additional medication, electroconvulsive therapy, therapy), functional status, patient satisfaction, and cost of care.

RESULTS: Men and women were somewhat different at baseline, although the authors did not report the characteristics of each treatment subgroup. Women were significantly more likely to have been treated for depression and to have a first-degree relative with depression, while men were more likely to be married and to have coexistent dysthymia. Follow-up was complete. Women responded better to sertraline than imipramine (57% improved vs 46%; P=.03; number needed to treat [NNT]=8), and men responded more to imipramine than to sertraline (62% vs 45%; P=.03; NNT=6). Women taking imipramine were more likely to withdraw from the study than those taking sertraline (26% vs 14%; P=.02; NNH=10), but women completing a course of imipramine still had a significantly poorer response than those taking sertraline. Men and women taking either drug showed no significant sex differences in overall frequency of treatment-emergent adverse events; however, more than 90% of all patients reported adverse effects, and adverse effects were the most common reason for withdrawal from the study. For men, imipramine caused significantly more dry mouth, dizziness, and constipation than sertralin, and a similarly high rate of sexual dysfunction and somnolence. For women, sertraline caused significantly more insomnia and diarrhea and less constipation and dry mouth than imipramine.