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Child Assessment of Dextromethorphan,. Diphenhydramine, and Placebo for. Nocturnal Cough Due to Upper. Respiratory Infection. Katharine E. Yoder1.
Child Assessment of Dextromethorphan, Diphenhydramine, and Placebo for Nocturnal Cough Due to Upper Respiratory Infection Katharine E. Yoder1 Michele L. Shaffer, PhD2 Susan J. La Tournous, RN1 Ian M. Paul, MD, MSc1,2

Summary: This study sought to investigate the efficacy of dextromethorphan (DM), diphenhydramine (DPH), and placebo (PL) for symptoms attributed to upper respiratory infections as determined by children, and to evaluate the concordance of perception of nocturnal symptoms between children and parents. A total of 37 children age 6 to 18 years of age were randomized in a double-masked fashion to receive a single bedtime dose of DM, DPH, or PL. Children found no significant difference in the effect of DM, DPH, or PL for any study outcome, and responses by parents and children were significantly correlated. Clin Pediatr. 2006;45:633-640

Introduction

N

octurnal cough and difficulty sleeping are common complaints by children with upper respirator y infections (URIs), and these illnesses are among the most common reasons for acute care pediatric visits. 1 Over-the-counter (OTC) cough and cold remedies, dextromethorphan (DM) and diphenhydramine (DPH), are

commonly administered by parents to relieve their children’s symptoms. The American Academy of Pediatrics (AAP), however, has questioned the use of OTC medicines in children with acute cough, largely due to the lack of evidence of benefit but also because of the potential for adverse effects associated with them.2 In evaluating the evidence that does exist, previous subjective studies on children with acute cough

have relied on parental assessment.3,4 Therefore, as part of a previously described investigation studying the effect of OTC medicines on children’s symptoms with cough due to URI,5 an assessment of the medicines by children was also performed. It was hypothesized that children would find more improvement in their nocturnal cough and sleep difficulty with DM and DPH than with placebo (PL). A strongly positive correlation between responses of children and their parents was also expected.

1Department of Pediatrics and 2Health Evaluation Sciences, Pennsylvania State University College of Medicine, Hershey, PA.

Reprint requests and correspondence to: Ian M. Paul, MD, MSc, Pediatrics, Penn State College of Medicine, H085, PO Box 850, Hershey, PA 17033. DOI: 10.1177/0009922806291014 © 2006 Sage Publications Please visit the Journal at http://cpj.sagepub.com

SEPTEMBER 2006

Methods Participants Patients were recruited from two pediatric acute care clinics af-

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Yo d e r e t a l . filiated with the Pennsylvania State University College of Medicine in Hershey, Pennsylvania, from June 2002 to May 2003. Eligible children were 6 to 18 years of age and were a subset of patients with a clinical diagnosis of cough due to URI enrolled in the study previously described by Paul et al.5

Study Design After parental informed consent and child assent were obtained, parental and child assessment of the child’s nocturnal cough and sleep difficulty on the previous night were obtained through questions on a 7-point Likert scale. The parental assessment has been previously described.5 Children could answer according to a visual scale of faces signifying degrees of symptom severity adapted from Wong and Baker 6 and a range of cor responding verbal responses (Figure 1). Verbal responses ranged from a “not at all” (0 points) to “extremely” (6 points). A higher

score indicated more severe symptoms and a lower score indicated lesser symptom severity. The visual scale was adapted from a 6point model to correspond with the parental 7-point Likert scale. This conversion was accomplished by creating a new face (number 3, “to some extent” on the scale) from the mouth and eye parts of faces adjacent to it. Children and their parents were asked about the child’s experience of (1) the frequency of coughing after bedtime the previous night, (2) sleep difficulty, (3) nighttime cough severity, and (4) the “bothersome” nature of the cough after bedtime. The parents and their children were questioned independently during their respective assessments to ensure that their responses did not influence one another. Three trained study coordinators and the principal investigator were responsible for survey administration. Stratification, medication dosing, and medication distribution are outlined in the study by Paul

et al.5 In brief, children were randomized in a double-masked fashion to receive DM (Benylin; Park Davis, Morris Plains, NJ), DPH (Diphen AF; Morton Grove Pharmaceuticals, Morton Grove, IL), or PL (Simple syrup NF; Humco, Texarkana, TX). DM was dosed by age based on label recommendations. DPH was dosed by weight as described by a standard pediatric reference.7 PL was administered in a dose volume equivalent to the dose volume of DM by age. A second survey asking the same questions was administered to assess nocturnal cough and sleep on the night after treatment was given. Again, parents and children were temporarily separated to ensure that their responses did not influence one another.

Statistical Analysis The children’s scores for the four outcome measures in the different treatment groups were compared by using one-way analysis of variance. The primary measure of interest was the evaluation

1. How much were you coughing after you went to bed last night? 2. How much did your cough make it hard for you to sleep last night? 3. How bad was your cough after you went to bed last night? 4. How much did your cough bother you after you went to bed last night? 0

1

2

3

4

5

Not at all

Not much

A little bit

To some extent

A lot

Very much

6

Extremely

Figure 1. Questions and accompanying visual scale with verbal responses used in child questionnaires. Each number corresponds to the 7-point Likert scale.

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N o c t u r n a l C o u g h i n C h i l d re n of cough frequency. Secondary measures included sleep difficulty, cough severity, and the amount of “bother” by the nocturnal cough. Symptom outcome measures were compared for differences from the first to second night by using a paired t-test. The agreement between parent and child reports of changes in the four outcome measures was measured by using concordance correlation coefficients.8 The magnitude and significance of the difference in parent and child responses across treatments groups was compared by using one-way analysis of variance. A positive difference indicated that the parents reported

more improvement than their children. The target sample size for the larger parental assessment study was selected to have 80% power to detect a 1-point difference between any two treatment groups with a 5% type I error rate. As the secondary analysis included only 37 of the 100 children randomized to participate in the larger parental assessment study, statistically insignificant results must be viewed with caution because of the increased probability of a type II error. This study met the approval of the Pennsylvania State University College of Medicine Institutional Review Board.

Results Thirty-seven children with nocturnal cough due to URI and their parents were included in this ancillary analysis. Twelve children received DM, 12 children received DPH, and 13 children received PL. On follow-up, all parents reported that their children received the medications. The median age of children was 7.50 years (range, 6.20–16.50 years) and approximately 59% of patients were female, with no signif icant difference of demographic characteristics between treatment groups (Table 1). In addition, no significant differences were found between baseline

Table 1

SELF-REPORTED DEMOGRAPHICS AND BASELINE CHARACTERISTICS DPH

DM

PL

p

7.35 ± 4.15

6.85 ± 3.65

9.50 ± 4.00

NS*

White

83

92

62

NS

Black/African American

8

0

0

Latino

0

0

23

Other

8

8

15

Female

67

67

46

Male

33

33

54

Duration of Illness (days; mean)

3.92

4.17

4.23

NS

Cough frequency score, mean

3.33

4.08

3.69

NS

Cough impact on child sleep score, mean

4.08

3.83

3.46

NS

Cough severity score, mean

3.83

3.92

3.38

NS

Cough “bothersome” to child score, mean

3.00

3.92

3.15

NS

Combined symptom score, mean

14.25

15.75

13.69

NS

Age (years; median ± quartile range) Race (%)

Gender (%) NS

*NS=not significant.

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Yo d e r e t a l . symptom severities and a combined symptom score in each treatment group (Table 1). Children’s subjective symptom scores from the night before enrollment when no medication had been given were compared to the scores for the subsequent night when treatment was given before bed. The scores for cough frequency, impact on sleep quality, cough severity, and “bothersome” nature of the cough were all significantly lower on the second night of the study for the entire cohort (Table 2). When comparing treatment groups, however, no significant differences were found for any of the outcomes (Figure 2). Children who received DM reported a 1.75-point improvement in cough frequency compared to improvements of 1.58 points and 1.38 points in those who received DPH and PL, respectively (p = 0.85). The children who received DPH reported 2.92 points improvement of sleep quality compared to 1.17 points of improvement by those taking DM and 1.15 points of improvement in those taking PL (p = 0.24). Similarly, those who received DPH noted a 2.17-point

improvement in cough severity, while the improvement reported by those who received PL and DM was 1.15 points and 0.75 points, respectively (p = 0.34). Children found an improvement in the “bothersome” nature of the cough of 1.92 points when taking DPH compared to improvements of 1.00 points for DM and 0.85 points for PL, although this trend toward greater improvement did not achieve statistical significance (p = 0.43). When the reported scores for all outcomes were combined, no significant difference between treatments was detected. The children who received DPH reported the greatest improvement of 8.58 points compared to an improvement of 4.67 points in those who received DM and 4.54 points of improvement in those who received PL (p = 0.32). Both children and their parents evaluated the change in subjective scores from the first night to the second night, and the results were compared. For each outcome, the scores of parents and children were significantly correlated for cough frequency (rccc = 0.60, p < 0.001), change in sleep quality (r ccc = 0.48, p =

0.001), cough severity (rccc = 0.51, p = 0.002), and “bothersome” nature of the cough (rccc = 0.49, p = 0.002) (Figure 3). Overall, there were trends toward greater reporting of symptom improvement between nights by parents (Table 3). In contrast, children who received DPH reported more improvement in sleep quality than noted by parents, and children who received DM noted slightly better improvement in their cough frequency than did their parents. However, none of these differences achieved statistical significance.

Discussion In this study, subjective responses of children with clinically diagnosed URI were used to investigate the efficacy of a single dose of DM and DPH compared to PL for nocturnal cough and sleep difficulty. While the entire cohort reported improved symptoms on the second night of the study, neither treatment with DM nor DPH was superior to PL for any of the study outcomes. In addition, a combined symptom

Table 2

COMPARISON BETWEEN CHILD RESPONSES ON THE FIRST (NO MEDICATION) AND SECOND (MEDICATION OR PLACEBO) NIGHTS OF THE STUDY FOR THE ENTIRE COHORT (N = 37)

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Outcome

1st Night

2nd Night

Difference

SD

p

Frequency

3.7

2.14

1.57

1.57