Levodropropizine vs Dextromethorphan in Dry Cough

Pulmonary Pharmacology & Therapeutics (1997) 10, 89–96
PULMONARY
PHARMACOLOGY
& THERAPEUTICS
Efficacy and Tolerability of Levodropropizine in Adult Patients
with Non-productive Cough. Comparison with
Dextromethorphan∗
E. Catena,† L. Daffonchio‡§
†Istituto di Clinica Tisiologica e Malattie Respiratorie, Seconda Università degli Studi, Napoli, Italy,
‡Research & Development Department, Dompé s.p.a., Milano, Italy
SUMMARY: The results of a double-blind, randomized clinical trial involving 209 adult patients of either sex
with moderate non-productive cough are reported. The therapeutic efficacy and the tolerability of levodropropizine
syrup (60 mg t.i.d. for 5 days) was evaluated in comparison with dextromethorphan syrup (15 mg t.i.d. for 5 days).
Efficacy was assessed by the number of coughing spells in a 6 h period, the cough frequency classes, the cough
intensity and the night awakenings due to cough. Tolerability was evaluated by laboratory results, vital signs and
any adverse event occurred during the clinical trial, including presence or absence of somnolence. Independently
from the underlying pathology and from the degree of baseline cough severity, the number of coughing spells was
significantly (P

90 E. Catena and L. Daffonchio
lung pathologies, but without relevant central side administered orally at the doses of 60 mg (10 ml) t.i.d.
effects. and 15 mg (5 ml) t.i.d., respectively, for 5 consecutive
5,6 Such a profile is likely to be accounted for
by a peripheral mechanism of action mainly involving days, according to the double-dummy technique. The
a peripheral inhibition of sensory C-fibre activation. 1st daily administration was given between 7.00 and
5,
7 Therefore, we carried out a multicentre clinical trial 9.00, the 2nd at 15.00 and the 3rd between 21.00 and
in a population of adult patients with moderate non- 23.00. The doses chosen for both drugs are within
productive cough, to confirm not only the efficacy the therapeutic dosages approved in Italy. A 5 day
of levodropropizine but also its tolerability and in treatment was chosen to test the symptomatic effect
particular the absence of central side effects.
PATIENTS AND METHODS
of the drugs, limiting the possibility that the amelioration
of cough could have been due only to an
improvement of the underlying disease.
Efficacy and tolerability of levodropropizine syrup Cough evaluation
administered in adult patients reporting with nonproductive
cough was evaluated in a double-blind,
randomized, parallel-group clinical trial conducted in
14 Italian centres. Levodropropizine was compared
with dextromethorphan syrup, chosen as a rep-
resentative centrally acting opioid compound. Dex-
tromethorphan is used world-wide as antitussive and
can be considered as a reference drug.
Patients recorded the actual number of coughing spells
per hour during 6 consecutive hours. In group A, this
assessment was performed in the morning, on entry
(baseline) and on the 2nd day of treatment. To optimize
this evaluation and to increase the patient’s
compliance with protocol procedures, patients in
group B counted the number of coughing spells in
2,8
The study was conducted in agreement with the
Good Clinical Practice guidelines and was approved
by an independent Ethics Committee prior to commencement.
the afternoon (from 15.00 to 21.00, after the 2nd daily
dose), on entry and on the 2nd and 5th day of
treatment.
Cough frequency classes and cough intensity were
also evaluated by the patient on entry (baseline) and
on each day of treatment. Cough frequency classes
Patients
were defined as: none, almost never (0–2 coughing
Subjects considered for inclusion were in- or outpatients,
aged between 18 and 75 years, of both sexes,
attending the study centres for diseases characterized
by moderate, severe or very severe non-productive
cough as graded by the investigator according to the
following scales: moderate (15–30 coughing spells/
day); severe (31–40 coughing spells/day); very severe
(>40 coughing spells/day) for the first 50 patients
enrolled (group A); moderate (5–10 coughing spells/
h); severe (11–20 coughing spells/h); very severe (>20
coughing spells/h) for the remaining 159 patients
spells/day), a little (3–14 coughing spells/day), enough
(15–30 coughing spells/day), much (31–40 coughing
spells/day), very much (>40 coughing spells/day).
Cough intensity was scored according to the following:
mild (cough with no strain and no noise), moderate
(cough with moderate strain and no noise), intense
(cough with much strain and noise).
On entry (baseline) and on each study day, the
number of night awakenings for coughing was also
reported by the patient.
(group B).
Patients with severe respiratory failure (progressive
Tolerability evaluation
dyspnoea), bronchial hypersecretion, secondary neo- Tolerability was assessed by recording any adverse
plasm, tuberculosis and asthma were excluded, as well event occurred during the study, observed directly
as patients with impaired cardiac, renal and hepatic by the investigator or reported by the patient, with
functions. Patients receiving a concomitant therapy particular attention paid to the symptom ‘som-
such as antitussives, mucoactives, antidepressants, 2 nolence’. The safety of both drugs was also assessed
agonists, antihistaminics and oral corticosteroids by analysing the results of pre- and post-treatment
(>20 mg prednisone or equivalent) were also excluded. clinical laboratory tests and physical examination.
All patients gave their verbal informed consent to Blood pressure and heart rate were recorded on adtake
part in the study, signed by an independent mission and on the 5th day of treatment.
witness.
The presence or the absence of somnolence, in-
tended as a decrease in daytime alertness, not-
Treatments
withstanding an adequate night sleep, was reported
by the patient, at admission and on each day of
Levodropropizine (Levotuss® syrup, 0.6%) and dex- treatment, and graded on a 3-point intensity scale as
tromethorphan (Fluprim® Tosse syrup, 0.3%) were follows: no somnolence, mild, or intense somnolence.

Overall efficacy/tolerability judgement
Antitussive Effect of Levodropropizine in Adult Patients 91
Table 1 Demographic characteristics and baseline features.
At the end of the experimental session, for group B Parameter Levodropropizine Dextromethorphan
only, an overall efficacy/tolerability judgement was
expressed by the investigator and by the patient as:
No. of cases and sex
(M/F)
110 (54/56) 99 (46/53)
disappearance of symptoms with or without adverse
events; improvement of symptoms with or without
adverse events; and unchanged symptoms with or
Age (years, mean±SD)
Height (cm, mean±SD)
Weight (kg, mean±SD)
Cough degree
55.1±14.8
163.3±8.3
69.9±12.7
54.0±15.9
164.3±8.3
71.3±12.4
a without adverse events.
(no. of
cases)
(moderate/severe/very
severe)
Statistical analysis
group A
group B
11/6/9
23/49/12
9/4/11
23/41/11
The time-profile of somnolence (presence or absence) Mean coughing spells/
hourb was analysed by means of Cochrane Q test for intra- (mean±SD)
treatment effect, and of Mantel-Haenszel chi-square
test for comparison between treatments. All other
variables, including somnolence intensity scale, were
group A
group B
Cough frequency
classes
6.7±4.1
14.4±11.5
1/23/13/71
8.8±6.6
14.2±6.3
2/21/16/59
b evaluated by means of ANOVA and Friedman test
(no. of cases)
(little/enough/much/very
followed by Schaffer multiple comparisons (intra- much)
Cough intensity b treatment time-profile). Differences between treat-
(no. of 32/48/28 23/47/28
ments were analysed by means of ANOVA and Mann-
Whitney’s U test.
Missing data were processed as such, since no
cases)
(mild/moderate/intense)
Night awakenings for
cough
2.7±1.7 3.1±2.1
b replacement of the missing values was considered
appropriate without introducing a bias in the treat-
(mean±SD)
Presence of somnolence
(no. of cases)
1/107 3/95
ment evaluation. All data were analysed according to (yes/no)
intention-to-treat criteria (all patients randomized). Underlying pathology
(% of cases)
—Upper respiratory 34.5 34.3
RESULTS
tract disorders
—Lower respiratory 44.5 39.4
Patients
tract disorders
—Neoplasm 5.5 6.1
—Others 15.5 20.2
Two hundred and nine in- and out-patients with nonproductive
cough (100 males and 109 females) were
recruited in the clinical trial. Mean age was 54.6 years
a b
Graded by the investigator; graded by the patient.
(range 18–82 years); 3 patients in levodropropizine possibly due to the difference in the criteria used
group (79, 78, 76 years, respectively) and 2 patients to classify cough degree on entry. All demographic
in dextromethorphan group (76 and 82 years, re- characteristics and baseline features, including basespectively)
were enrolled at ages higher than 75 years, line values of cough and somnolence-related para-
representing a minor deviation to the protocol. Out meters, were homogeneous in both patients assigned
of the 209 enrolled patients, 110 were treated with
levodropropizine and 99 with dextromethorphan.
to levodropropizine or dextromethorphan (Table 1).
As shown in Table 1, upper and lower respiratory
tract disorders were the most frequent underlying
Cough evaluation
pathologies in both treatment groups. Upper res- The antitussive effectiveness of levodropropizine is
piratory diseases were mainly represented by acute firstly demonstrated by the quantitative evaluation of
pharyngitis, laryngitis and tracheitis or chronic atro- the actual number of coughing spells (Fig. 1; Table
phic laryngitis and rhino-pharyngitis secondary to 2). In fact, already after the 2nd day of treatment,
chronic sinusitis or ear-nose disorders. Lower res- patients in both group A and B experienced a stat-
piratory pathologies were mainly represented by acute istically significant (P

92 E. Catena and L. Daffonchio
Coughing spells
16
14
12
10
8
6
4
2
1 h 2 h3 h4 h5 h6 h
Baseline
1 h 2 h3 h4 h5 h6 h
Day 2
1 h 2 h3 h4 h5 h6 h
Day 5
Fig. 1 Number of coughing spells. Coughing spells were recorded by the patient during a 6 h period. Values represent the mean±SE
on all available data within the two groups of patients identified (open symbol, group A, n=22–24; closed symbol, group B, n=73–84).
The number of coughing spells decreased significantly for both drugs (P

Table 4 Cough intensity evaluated by the patient. Tolerability evaluation
Antitussive Effect of Levodropropizine in Adult Patients 93
Levodropropizine
(no. of patients)
Dextromethorphan
(no. of patients)
Overall, 16 patients reported adverse events, leading
to treatment interruption in two cases, both of them
Cough intensity 0 1
Day
2 3 4 5 0 1
Day
2 3 4 5
in the dextromethorphan group. Adverse events were
mostly represented by somnolence (15 patients) and
Mild 32 35 52 70 85 88 23 23 35 52 65 71 were not distributed homogeneously between treat-
Moderate
Intense
P vs Day 0
48 48 47 30 17 15
28 25 9 6 4 2
ns ∗ ∗∗∗∗∗∗
47 51 52 39 28 21
28 24 11 5 3 2
ns ns ∗∗ ∗∗ ∗∗
ment groups. Indeed, significantly (P

94 E. Catena and L. Daffonchio
Percent of somnolent patients
12
10
8
6
4
2
0
Baseline
Day 1
Day 2
Fig. 3 Somnolence. Presence or absence of somnolence during each treatment day was reported by the patient. No significant
difference was reached between treatment groups, except on day 4 where the percentage of patients reporting somnolence during
dextromethorphan treatment was significantly (∗P

Antitussive Effect of Levodropropizine in Adult Patients 95
nificant effect earlier (within 2 days) than importance from both the quality of life and from the
dextromethorphan (at the 3rd day). The amelioration safety profile. This evidence is further supported by
of coughing intensity is important from the therapeutic the fact that somnolence was always judged mild in
point of view, since a high intrathoracic pressure may levodropropizine group, while the few cases of intense
have deleterious consequences and it seems to be somnolence were related only to dextromethorphan
appreciated subjectively by the patients. 10
administration.
Concurrently with the relief of daily cough, levo- In conclusion, results obtained in this study confirm
dropropizine also improved the quality of sleep. In- the antitussive efficacy of levodropropizine which is
deed, the night awakenings due to cough, a symptom as effective as, or even more effective than, dextropresented
by two-thirds of the patients, decreased methorphan in ameliorating cough symptom. Morewith
time, significantly more with levodropropizine over, present data further support a more favourthan
with dextromethorphan. able benefit/risk profile of levodropropizine as com-
Lack of a placebo control group might represent a
limitation of this trial; indeed, the possibility that
cough reduction could be attributed, at least in part,
pared with dextromethorphan.
to a spontaneous relief cannot be ruled out, mainly
in acute pathologies. However, a placebo group was
PARTICIPATING INVESTIGATORS
not included in this study whose end-point was the
comparison between two drugs, for which the efficacy
has been previously demonstrated in double-blind,
placebo-controlled trials.
E. Catena, R. Maselli, G. Saviano: Istituto di Clinica
Tisiologica e Malattie Respiratorie, Seconda Un-
iversità degli Studi, Napoli. F. Bariffi: Cattedra di
5,6,8,11,12 Moreover, the time
course of the antitussive effect makes it improbable
that the improvement in cough was due only to the
Malattie Respiratorie, Università di Napoli ‘Federico
II’. V. Rocco: Divisione di Fisiopatologia Respiratoria,
Ospedale V. Monaldi, Napoli. G. B. Cavassini: IIa natural resolution of the underlying disease, since
relief from cough was already evident within 2–3
days, considering both quantitative and qualitative
parameters.
Concerning the general safety, results from the
analysis of the vital signs (heart rate and blood pressure)
as well as of the laboratory tests confirm the
good tolerability for both drugs. On the other hand,
significantly less patients (3.6%) complained of adverse
events in the levodropropizine group than with dextromethorphan
(12.1%). Extrapolating these results
to the general population who would use the two
antitussive drugs, the relative risk of adverse events
related to the use of dextromethorphan can be es-
timated to be approximately 3.5 times higher than
with levodropropizine. This finding supports a better
Divisione di Medicina Interna, Ospedale Consorziale,
Bentivoglio (BO). E. Farina: Divisione di Pne-
umologia, Ospedale San Salvatore, L’Aquila. E.
Marchi: Centro per lo Studio delle Broncopneumopatie
Senili, Casatenovo (LC). A. Ciaccia:
Clinica di Malattie dell’Apparato Respiratorio, Po-
liclinico S. Anna, Ferrara. P. Spina: Divisione di
Medicina Generale, Ospedale Civile, Poggio Rusco
(MN). R. Zuin: Istituto di Pneumologia, Università
di Padova. A. Mezzasalma: Divisione di Oto-
rinolaringoiatria, Ospedale Maggiore, Modica (RG).
F. Foresti: Divisione di Medicina Generale, Ospedale
Civile, Vittoria (RG). G. D’Addetta: Divisione di Medicina,
Ospedale Civile, Monte S. Angelo (FG). G.
Cattini: Divisione di Pneumologia, Ospedale Bellaria,
Bologna. F. Sisti: Divisione di Pneumologia, Presidio
safety profile for levodropropizine than for de-
Ospedaliero Multizonale ‘D. Cotugno’, Bari.
xtromethorphan, particularly as far as central side
effects are concerned, taking into account that somnolence
was by far the most frequent adverse event
reported.
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