Dextromethorphan and Codeine: Objective Assessment of. Antitussive Activity in Patients with Chronic Cough. Heinrich Matthys, MD, Professor of Medicine, ...
J Int Med Res (1983) 11,92
Dextromethorphan and Codeine: Objective Assessment of Antitussive Activity in Patients with Chronic Cough Heinrich Matthys, MD, Professor of Medicine, Director of Clinic. Barbel Bleicher, MD, Physician and Ulrich Bleicher, MD, Physician, Department of Pulmonary Disease, University , Medical Clinic. D-7800 Freiburg i Br, West Germany
Dextromethorphan, the most widely used cough suppressant in the U.SA., was compared with codeine, the traditional European antitussive, in a doubleblind. crossover trial using both an objective and subjective assessment of efficacy in sixteen patients with chronic, stable cough, Both preparations, at a dose of 20 mg. were similarly effective in reducing cough frequency. Dextromethorphan lowered cough intensity to a greater degree than codeine (p < 0·0008) and was considered the better antitussive by the majority of patients (p < 0·001). In view of its lack of side-effects. its safety even in overdose and its non-narcotic status, the increasing trend in Europe to use dextromethorphan as a substitute for codeine in the treatment of cough is to be welcomed.
Introduction Dextromethorphan has established itself as an effective and safe antitussive agent during the past 25 years. In the U.S.A., where it is available without prescription, it is by far the most commonly used antitussive. In contrast, it is less well known in other countries, where codeine or its derivatives are still more commonly used. Not only does codeine tend to cause constipation but also it has been reported to be a common cause of death by accidental overdose in young children (Miihlendahl et al 1976, Miihlendahl & Krienke 1978), and it has been incriminated as the first drug misused by subsequent addicts (Bickerman 1974).
Postal address for reprint requests: Herrn Prof Dr med H Matthys, Aerztlicher Direktor, Medizinische Universitatsklinik, Abteilung Pulrnologie, Hugstetter Strasse 55, D-7800 Freiburg i Br. West Germany.
Dextromethorphan, on the contrary, is well tolerated, has a good safety record even in overdose, and is non-narcotic (Department of Health, Education and Welfare; Food and Drug Administration 1976). In view of the present increasing use of dextromethorphan in European countries, we have compared its efficacy with that of codeine using a modern method of objective assessment in addition to the subjective judgement of the patients. Patients and Methods The investigations were carried out in eleven male and five female patients with chronic, stable cough due to pulmonary tuberculosis, bronchial carcinoma or obstructive lung disease. Their mean age was 55 ·9 ± 17·2 years (range 25-74) and mean weight was 66·2 ± 10·3 kg (range 46-79). The individual details and smoking habits are shown in Table 1. All patients gave their informed consent to participate in the trial.
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H Matthys, B Bleicher and U Bleicher Table 1 Details of patients investigated
Patient I
2 3 4 5 6 7 8 9 10 11
12 13 14 IS
16
Sex·
Age (years)
(kg)
Diagnosis
M F M M M M M M F M M F M M F F
47 25 36 67 68 71 30 62 68 74 52 67 63 67 70 27
76 59 76 71 79 58 74 75 46 49 60 79 65 60 68 64
Pulmonary TB Pulmonary TB Pulmonary TB Pulmonary TB Ca bronchus Ca bronchus Ca bronchus Ca bronchus Pulmonary fibrosis Asthma Asthma Asthma Asthma + bronchitis Bronchitis Bronchitis Pollen allergy
·M = male, F = female "Smoker +, previous smoker
Weight Smokers"
+ -
-
± ± ± ± ±
-
+ -
± ±
-
±, non-smoker -
The study was of double-blind, crossover design, each patient receiving on three consecutive nights two doses of 20 mg dextromethorphan hydrobromide, 20 mg codeine phosphate and placebo. The preparations were administered in visually identical capsules at 22.00 hand 02.00 h; no antitussive was administered during the following 20 hours. Although no carry-over effect was expected, the patients were randomized to sequences of latin square design. During the whole study period alcohol and sleeping tablets were not allowed, and medication influencing the cough was discontinued. Cough was measured by means of a pressure transducer attached over the trachea and connected to a single-channel recorder which registered cough frequency, and amplitude on a scale of 0 to 10. The method has been described in detail (Riihle, Graber & Matthys 1977, Matthys, Kohler & Riihle 1979, Matthys 1982). The recording was made during the 8 hours from 22.00 h until 06.00 h; during this period air temperature and
humidity remained more or less constant and smoking was forbidden. Throughout each night the patients were attended by the same doctor to ensure correct administration of the capsules and to record symptoms and preparation preference. The data were evaluated by an analysis of variance using the general linear model of the Statistical Analysis System Institute (Freund & Littel 1981) and by Fisher's exact probability test. Results
The numbers of coughs recorded each hour for the sixteen individual patients are shown in Table 2 and the mean values are plotted in Figure 1. Dextromethorphan suppressed cough frequency slightly more than did codeine throughout almost the whole 8-hour recording time, but the difference was not significant. Both preparations were significantly more effective than placebo (p < 0·000 1), . and their onset of action was apparent during the first hour after administration.
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94
The Journal ofI nternational Medical Research
Table 2 Cough frequency (per hour)
Hour Patient
1
Preparation-
0 C P
2
0
4
C P 0 C P 0
5
P 0
3
C C 6 7
P 0 C P 0 C
p
8 9 10
0 C P 0 C P 0
C 11
12
P 0 C P 0 C P
13 14 15
0 C P 0
C p 0 C
16
P 0 C P
Mean ±S.O.
0
C p
-0 = dextromethorphan
13 9 10 5 4 1 22 27 20 1 2 2 12 9 9 5 6 2 3 2 4 3 3 4 16 23 19 12 9 9 8 7 9 12 17 16 12 9 14 23 18 29 4 6 3 1 6 2 9·5 ±6·9 9·8 ±7·5 9·6 ±S·1
J
2
1
8 9 12 6 4 4 9 15 29 2 0 1 10 9 9 4 4 6 1 2 0 4 4 5 7 14 18 9 9 9 8 8 10 9 8 17
6 6 9 2 4 2 7 7 16 1 0 2 9 10 21 4 4 7 0 0 2 3 2 3 5 10 19 7 8 10 5 7 7 10 8 13 12
10
11
13 23 19 19 4 4 5 0 7 3
15 16 16 27 4 3 4 0 6 2
5 7 9 2 2 4 9 4 15 0 1 0 6 9 9 3 4 5 0 2 1 5 2 3 3 9 34 6 9 9 5 3 8 10 9 12 14 9 12 19 16 25 3 5 5 0 2 3
7·2 ±5·4 7·9 ±5·0 10·0 ±7·8
5·7 H·4 6·4 H·2 9·9 ±7·8
5·6 ±5·2 5·8 H·l 9·6 ±9·0
11
C = codeine
4
5
6
7
8
4 15 10 9 19 24 14 22 4 4 5 0 2 0
2 3 12 0 2 5 5 7 9 0 2 1 3 6 9 2 4 5 0 1 2 2 2 6 4 4 21 5 6 12 2 4 5 8 5 14 7 10 15 9 15 25 5 2 5 0 4 0
4 3 11 0 3 3 4 4 14 0 0 3 5 6 12 1 4 7 0 1 3 0 1 6 3 6 23 5 3 11 2 4 5 6 9 14 6 8 16 16 16 3 4 6 0 4 2
4 5 18 1 1 4 7 5 27 0 1 2 3 6 19 0 2 11 0 2 0 2 1 15 3 6 37 4 3 14 2 5 9 7 6 21 7 8 32 12 19 28 3 4 5 0 4 1
4·9 ±6·3 4·9 ±3·7 8·2 ±6·4
3·4 ±2·9 4·8 ±3·6 9·1 ± 7·1
3·3 ±3·4 4·8 ±3·8 9·5 H·l
3·4 ±3·4 4·9 H·3 15·2 ± 11·6
6 4 7 1 0 6 5 7 9 0 1 2 8 7 12 1 5 4 0 0 0 0 3 4 5 9 12 4 5 9 0 5 5 11
P = placebo
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13
H Matthys, B Bleicher and U Bleicher
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Time after first administration (hours) Fig 1 Mean cough frequency of sixteen patients after treatment with 20 mg dextromethorphan ( "'--"'), 20 mg codeine (0 - - - - 0) and placebo (. 0 0 0.)0 There was no significant difference between the antitussives, but they were both significantly more effective than placebo (p
