Levodropropizine vs Dextromethorphan in Dry Cough
Levodropropizine vs Dextromethorphan in Dry Cough
Levodropropizine vs Dextromethorphan in Dry Cough
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Pulmonary Pharmacology & Therapeutics (1997) 10, 89–96<br />
PULMONARY<br />
PHARMACOLOGY<br />
& THERAPEUTICS<br />
Efficacy and Tolerability of <strong>Levodropropiz<strong>in</strong>e</strong> <strong>in</strong> Adult Patients<br />
with Non-productive <strong>Cough</strong>. Comparison with<br />
<strong>Dextromethorphan</strong>∗<br />
E. Catena,† L. Daffonchio‡§<br />
†Istituto di Cl<strong>in</strong>ica Tisiologica e Malattie Respiratorie, Seconda Università degli Studi, Napoli, Italy,<br />
‡Research & Development Department, Dompé s.p.a., Milano, Italy<br />
SUMMARY: The results of a double-bl<strong>in</strong>d, randomized cl<strong>in</strong>ical trial <strong>in</strong>volv<strong>in</strong>g 209 adult patients of either sex<br />
with moderate non-productive cough are reported. The therapeutic efficacy and the tolerability of levodropropiz<strong>in</strong>e<br />
syrup (60 mg t.i.d. for 5 days) was evaluated <strong>in</strong> comparison with dextromethorphan syrup (15 mg t.i.d. for 5 days).<br />
Efficacy was assessed by the number of cough<strong>in</strong>g spells <strong>in</strong> a 6 h period, the cough frequency classes, the cough<br />
<strong>in</strong>tensity and the night awaken<strong>in</strong>gs due to cough. Tolerability was evaluated by laboratory results, vital signs and<br />
any adverse event occurred dur<strong>in</strong>g the cl<strong>in</strong>ical trial, <strong>in</strong>clud<strong>in</strong>g presence or absence of somnolence. Independently<br />
from the underly<strong>in</strong>g pathology and from the degree of basel<strong>in</strong>e cough severity, the number of cough<strong>in</strong>g spells was<br />
significantly (P
90 E. Catena and L. Daffonchio<br />
lung pathologies, but without relevant central side adm<strong>in</strong>istered orally at the doses of 60 mg (10 ml) t.i.d.<br />
effects. and 15 mg (5 ml) t.i.d., respectively, for 5 consecutive<br />
5,6 Such a profile is likely to be accounted for<br />
by a peripheral mechanism of action ma<strong>in</strong>ly <strong>in</strong>volv<strong>in</strong>g days, accord<strong>in</strong>g to the double-dummy technique. The<br />
a peripheral <strong>in</strong>hibition of sensory C-fibre activation. 1st daily adm<strong>in</strong>istration was given between 7.00 and<br />
5,<br />
7 Therefore, we carried out a multicentre cl<strong>in</strong>ical trial 9.00, the 2nd at 15.00 and the 3rd between 21.00 and<br />
<strong>in</strong> a population of adult patients with moderate non- 23.00. The doses chosen for both drugs are with<strong>in</strong><br />
productive cough, to confirm not only the efficacy the therapeutic dosages approved <strong>in</strong> Italy. A 5 day<br />
of levodropropiz<strong>in</strong>e but also its tolerability and <strong>in</strong> treatment was chosen to test the symptomatic effect<br />
particular the absence of central side effects.<br />
PATIENTS AND METHODS<br />
of the drugs, limit<strong>in</strong>g the possibility that the amelioration<br />
of cough could have been due only to an<br />
improvement of the underly<strong>in</strong>g disease.<br />
Efficacy and tolerability of levodropropiz<strong>in</strong>e syrup <strong>Cough</strong> evaluation<br />
adm<strong>in</strong>istered <strong>in</strong> adult patients report<strong>in</strong>g with nonproductive<br />
cough was evaluated <strong>in</strong> a double-bl<strong>in</strong>d,<br />
randomized, parallel-group cl<strong>in</strong>ical trial conducted <strong>in</strong><br />
14 Italian centres. <strong>Levodropropiz<strong>in</strong>e</strong> was compared<br />
with dextromethorphan syrup, chosen as a rep-<br />
resentative centrally act<strong>in</strong>g opioid compound. Dex-<br />
tromethorphan is used world-wide as antitussive and<br />
can be considered as a reference drug.<br />
Patients recorded the actual number of cough<strong>in</strong>g spells<br />
per hour dur<strong>in</strong>g 6 consecutive hours. In group A, this<br />
assessment was performed <strong>in</strong> the morn<strong>in</strong>g, on entry<br />
(basel<strong>in</strong>e) and on the 2nd day of treatment. To optimize<br />
this evaluation and to <strong>in</strong>crease the patient’s<br />
compliance with protocol procedures, patients <strong>in</strong><br />
group B counted the number of cough<strong>in</strong>g spells <strong>in</strong><br />
2,8<br />
The study was conducted <strong>in</strong> agreement with the<br />
Good Cl<strong>in</strong>ical Practice guidel<strong>in</strong>es and was approved<br />
by an <strong>in</strong>dependent Ethics Committee prior to commencement.<br />
the afternoon (from 15.00 to 21.00, after the 2nd daily<br />
dose), on entry and on the 2nd and 5th day of<br />
treatment.<br />
<strong>Cough</strong> frequency classes and cough <strong>in</strong>tensity were<br />
also evaluated by the patient on entry (basel<strong>in</strong>e) and<br />
on each day of treatment. <strong>Cough</strong> frequency classes<br />
Patients<br />
were def<strong>in</strong>ed as: none, almost never (0–2 cough<strong>in</strong>g<br />
Subjects considered for <strong>in</strong>clusion were <strong>in</strong>- or outpatients,<br />
aged between 18 and 75 years, of both sexes,<br />
attend<strong>in</strong>g the study centres for diseases characterized<br />
by moderate, severe or very severe non-productive<br />
cough as graded by the <strong>in</strong>vestigator accord<strong>in</strong>g to the<br />
follow<strong>in</strong>g scales: moderate (15–30 cough<strong>in</strong>g spells/<br />
day); severe (31–40 cough<strong>in</strong>g spells/day); very severe<br />
(>40 cough<strong>in</strong>g spells/day) for the first 50 patients<br />
enrolled (group A); moderate (5–10 cough<strong>in</strong>g spells/<br />
h); severe (11–20 cough<strong>in</strong>g spells/h); very severe (>20<br />
cough<strong>in</strong>g spells/h) for the rema<strong>in</strong><strong>in</strong>g 159 patients<br />
spells/day), a little (3–14 cough<strong>in</strong>g spells/day), enough<br />
(15–30 cough<strong>in</strong>g spells/day), much (31–40 cough<strong>in</strong>g<br />
spells/day), very much (>40 cough<strong>in</strong>g spells/day).<br />
<strong>Cough</strong> <strong>in</strong>tensity was scored accord<strong>in</strong>g to the follow<strong>in</strong>g:<br />
mild (cough with no stra<strong>in</strong> and no noise), moderate<br />
(cough with moderate stra<strong>in</strong> and no noise), <strong>in</strong>tense<br />
(cough with much stra<strong>in</strong> and noise).<br />
On entry (basel<strong>in</strong>e) and on each study day, the<br />
number of night awaken<strong>in</strong>gs for cough<strong>in</strong>g was also<br />
reported by the patient.<br />
(group B).<br />
Patients with severe respiratory failure (progressive<br />
Tolerability evaluation<br />
dyspnoea), bronchial hypersecretion, secondary neo- Tolerability was assessed by record<strong>in</strong>g any adverse<br />
plasm, tuberculosis and asthma were excluded, as well event occurred dur<strong>in</strong>g the study, observed directly<br />
as patients with impaired cardiac, renal and hepatic by the <strong>in</strong>vestigator or reported by the patient, with<br />
functions. Patients receiv<strong>in</strong>g a concomitant therapy particular attention paid to the symptom ‘som-<br />
such as antitussives, mucoactives, antidepressants, 2 nolence’. The safety of both drugs was also assessed<br />
agonists, antihistam<strong>in</strong>ics and oral corticosteroids by analys<strong>in</strong>g the results of pre- and post-treatment<br />
(>20 mg prednisone or equivalent) were also excluded. cl<strong>in</strong>ical laboratory tests and physical exam<strong>in</strong>ation.<br />
All patients gave their verbal <strong>in</strong>formed consent to Blood pressure and heart rate were recorded on adtake<br />
part <strong>in</strong> the study, signed by an <strong>in</strong>dependent mission and on the 5th day of treatment.<br />
witness.<br />
The presence or the absence of somnolence, <strong>in</strong>-<br />
tended as a decrease <strong>in</strong> daytime alertness, not-<br />
Treatments<br />
withstand<strong>in</strong>g an adequate night sleep, was reported<br />
by the patient, at admission and on each day of<br />
<strong>Levodropropiz<strong>in</strong>e</strong> (Levotuss® syrup, 0.6%) and dex- treatment, and graded on a 3-po<strong>in</strong>t <strong>in</strong>tensity scale as<br />
tromethorphan (Fluprim® Tosse syrup, 0.3%) were follows: no somnolence, mild, or <strong>in</strong>tense somnolence.
Overall efficacy/tolerability judgement<br />
Antitussive Effect of <strong>Levodropropiz<strong>in</strong>e</strong> <strong>in</strong> Adult Patients 91<br />
Table 1 Demographic characteristics and basel<strong>in</strong>e features.<br />
At the end of the experimental session, for group B Parameter <strong>Levodropropiz<strong>in</strong>e</strong> <strong>Dextromethorphan</strong><br />
only, an overall efficacy/tolerability judgement was<br />
expressed by the <strong>in</strong>vestigator and by the patient as:<br />
No. of cases and sex<br />
(M/F)<br />
110 (54/56) 99 (46/53)<br />
disappearance of symptoms with or without adverse<br />
events; improvement of symptoms with or without<br />
adverse events; and unchanged symptoms with or<br />
Age (years, mean±SD)<br />
Height (cm, mean±SD)<br />
Weight (kg, mean±SD)<br />
<strong>Cough</strong> degree<br />
55.1±14.8<br />
163.3±8.3<br />
69.9±12.7<br />
54.0±15.9<br />
164.3±8.3<br />
71.3±12.4<br />
a without adverse events.<br />
(no. of<br />
cases)<br />
(moderate/severe/very<br />
severe)<br />
Statistical analysis<br />
group A<br />
group B<br />
11/6/9<br />
23/49/12<br />
9/4/11<br />
23/41/11<br />
The time-profile of somnolence (presence or absence) Mean cough<strong>in</strong>g spells/<br />
hourb was analysed by means of Cochrane Q test for <strong>in</strong>tra- (mean±SD)<br />
treatment effect, and of Mantel-Haenszel chi-square<br />
test for comparison between treatments. All other<br />
variables, <strong>in</strong>clud<strong>in</strong>g somnolence <strong>in</strong>tensity scale, were<br />
group A<br />
group B<br />
<strong>Cough</strong> frequency<br />
classes<br />
6.7±4.1<br />
14.4±11.5<br />
1/23/13/71<br />
8.8±6.6<br />
14.2±6.3<br />
2/21/16/59<br />
b evaluated by means of ANOVA and Friedman test<br />
(no. of cases)<br />
(little/enough/much/very<br />
followed by Schaffer multiple comparisons (<strong>in</strong>tra- much)<br />
<strong>Cough</strong> <strong>in</strong>tensity b treatment time-profile). Differences between treat-<br />
(no. of 32/48/28 23/47/28<br />
ments were analysed by means of ANOVA and Mann-<br />
Whitney’s U test.<br />
Miss<strong>in</strong>g data were processed as such, s<strong>in</strong>ce no<br />
cases)<br />
(mild/moderate/<strong>in</strong>tense)<br />
Night awaken<strong>in</strong>gs for<br />
cough<br />
2.7±1.7 3.1±2.1<br />
b replacement of the miss<strong>in</strong>g values was considered<br />
appropriate without <strong>in</strong>troduc<strong>in</strong>g a bias <strong>in</strong> the treat-<br />
(mean±SD)<br />
Presence of somnolence<br />
(no. of cases)<br />
1/107 3/95<br />
ment evaluation. All data were analysed accord<strong>in</strong>g to (yes/no)<br />
<strong>in</strong>tention-to-treat criteria (all patients randomized). Underly<strong>in</strong>g pathology<br />
(% of cases)<br />
—Upper respiratory 34.5 34.3<br />
RESULTS<br />
tract disorders<br />
—Lower respiratory 44.5 39.4<br />
Patients<br />
tract disorders<br />
—Neoplasm 5.5 6.1<br />
—Others 15.5 20.2<br />
Two hundred and n<strong>in</strong>e <strong>in</strong>- and out-patients with nonproductive<br />
cough (100 males and 109 females) were<br />
recruited <strong>in</strong> the cl<strong>in</strong>ical trial. Mean age was 54.6 years<br />
a b<br />
Graded by the <strong>in</strong>vestigator; graded by the patient.<br />
(range 18–82 years); 3 patients <strong>in</strong> levodropropiz<strong>in</strong>e possibly due to the difference <strong>in</strong> the criteria used<br />
group (79, 78, 76 years, respectively) and 2 patients to classify cough degree on entry. All demographic<br />
<strong>in</strong> dextromethorphan group (76 and 82 years, re- characteristics and basel<strong>in</strong>e features, <strong>in</strong>clud<strong>in</strong>g basespectively)<br />
were enrolled at ages higher than 75 years, l<strong>in</strong>e values of cough and somnolence-related para-<br />
represent<strong>in</strong>g a m<strong>in</strong>or deviation to the protocol. Out meters, were homogeneous <strong>in</strong> both patients assigned<br />
of the 209 enrolled patients, 110 were treated with<br />
levodropropiz<strong>in</strong>e and 99 with dextromethorphan.<br />
to levodropropiz<strong>in</strong>e or dextromethorphan (Table 1).<br />
As shown <strong>in</strong> Table 1, upper and lower respiratory<br />
tract disorders were the most frequent underly<strong>in</strong>g<br />
<strong>Cough</strong> evaluation<br />
pathologies <strong>in</strong> both treatment groups. Upper res- The antitussive effectiveness of levodropropiz<strong>in</strong>e is<br />
piratory diseases were ma<strong>in</strong>ly represented by acute firstly demonstrated by the quantitative evaluation of<br />
pharyngitis, laryngitis and tracheitis or chronic atro- the actual number of cough<strong>in</strong>g spells (Fig. 1; Table<br />
phic laryngitis and rh<strong>in</strong>o-pharyngitis secondary to 2). In fact, already after the 2nd day of treatment,<br />
chronic s<strong>in</strong>usitis or ear-nose disorders. Lower res- patients <strong>in</strong> both group A and B experienced a stat-<br />
piratory pathologies were ma<strong>in</strong>ly represented by acute istically significant (P
92 E. Catena and L. Daffonchio<br />
<strong>Cough</strong><strong>in</strong>g spells<br />
16<br />
14<br />
12<br />
10<br />
8<br />
6<br />
4<br />
2<br />
1 h 2 h3 h4 h5 h6 h<br />
Basel<strong>in</strong>e<br />
1 h 2 h3 h4 h5 h6 h<br />
Day 2<br />
1 h 2 h3 h4 h5 h6 h<br />
Day 5<br />
Fig. 1 Number of cough<strong>in</strong>g spells. <strong>Cough</strong><strong>in</strong>g spells were recorded by the patient dur<strong>in</strong>g a 6 h period. Values represent the mean±SE<br />
on all available data with<strong>in</strong> the two groups of patients identified (open symbol, group A, n=22–24; closed symbol, group B, n=73–84).<br />
The number of cough<strong>in</strong>g spells decreased significantly for both drugs (P
Table 4 <strong>Cough</strong> <strong>in</strong>tensity evaluated by the patient. Tolerability evaluation<br />
Antitussive Effect of <strong>Levodropropiz<strong>in</strong>e</strong> <strong>in</strong> Adult Patients 93<br />
<strong>Levodropropiz<strong>in</strong>e</strong><br />
(no. of patients)<br />
<strong>Dextromethorphan</strong><br />
(no. of patients)<br />
Overall, 16 patients reported adverse events, lead<strong>in</strong>g<br />
to treatment <strong>in</strong>terruption <strong>in</strong> two cases, both of them<br />
<strong>Cough</strong> <strong>in</strong>tensity 0 1<br />
Day<br />
2 3 4 5 0 1<br />
Day<br />
2 3 4 5<br />
<strong>in</strong> the dextromethorphan group. Adverse events were<br />
mostly represented by somnolence (15 patients) and<br />
Mild 32 35 52 70 85 88 23 23 35 52 65 71 were not distributed homogeneously between treat-<br />
Moderate<br />
Intense<br />
P <strong>vs</strong> Day 0<br />
48 48 47 30 17 15<br />
28 25 9 6 4 2<br />
ns ∗ ∗∗∗∗∗∗<br />
47 51 52 39 28 21<br />
28 24 11 5 3 2<br />
ns ns ∗∗ ∗∗ ∗∗<br />
ment groups. Indeed, significantly (P
94 E. Catena and L. Daffonchio<br />
Percent of somnolent patients<br />
12<br />
10<br />
8<br />
6<br />
4<br />
2<br />
0<br />
Basel<strong>in</strong>e<br />
Day 1<br />
Day 2<br />
Fig. 3 Somnolence. Presence or absence of somnolence dur<strong>in</strong>g each treatment day was reported by the patient. No significant<br />
difference was reached between treatment groups, except on day 4 where the percentage of patients report<strong>in</strong>g somnolence dur<strong>in</strong>g<br />
dextromethorphan treatment was significantly (∗P
Antitussive Effect of <strong>Levodropropiz<strong>in</strong>e</strong> <strong>in</strong> Adult Patients 95<br />
nificant effect earlier (with<strong>in</strong> 2 days) than importance from both the quality of life and from the<br />
dextromethorphan (at the 3rd day). The amelioration safety profile. This evidence is further supported by<br />
of cough<strong>in</strong>g <strong>in</strong>tensity is important from the therapeutic the fact that somnolence was always judged mild <strong>in</strong><br />
po<strong>in</strong>t of view, s<strong>in</strong>ce a high <strong>in</strong>trathoracic pressure may levodropropiz<strong>in</strong>e group, while the few cases of <strong>in</strong>tense<br />
have deleterious consequences and it seems to be somnolence were related only to dextromethorphan<br />
appreciated subjectively by the patients. 10<br />
adm<strong>in</strong>istration.<br />
Concurrently with the relief of daily cough, levo- In conclusion, results obta<strong>in</strong>ed <strong>in</strong> this study confirm<br />
dropropiz<strong>in</strong>e also improved the quality of sleep. In- the antitussive efficacy of levodropropiz<strong>in</strong>e which is<br />
deed, the night awaken<strong>in</strong>gs due to cough, a symptom as effective as, or even more effective than, dextropresented<br />
by two-thirds of the patients, decreased methorphan <strong>in</strong> ameliorat<strong>in</strong>g cough symptom. Morewith<br />
time, significantly more with levodropropiz<strong>in</strong>e over, present data further support a more favourthan<br />
with dextromethorphan. able benefit/risk profile of levodropropiz<strong>in</strong>e as com-<br />
Lack of a placebo control group might represent a<br />
limitation of this trial; <strong>in</strong>deed, the possibility that<br />
cough reduction could be attributed, at least <strong>in</strong> part,<br />
pared with dextromethorphan.<br />
to a spontaneous relief cannot be ruled out, ma<strong>in</strong>ly<br />
<strong>in</strong> acute pathologies. However, a placebo group was<br />
PARTICIPATING INVESTIGATORS<br />
not <strong>in</strong>cluded <strong>in</strong> this study whose end-po<strong>in</strong>t was the<br />
comparison between two drugs, for which the efficacy<br />
has been previously demonstrated <strong>in</strong> double-bl<strong>in</strong>d,<br />
placebo-controlled trials.<br />
E. Catena, R. Maselli, G. Saviano: Istituto di Cl<strong>in</strong>ica<br />
Tisiologica e Malattie Respiratorie, Seconda Un-<br />
iversità degli Studi, Napoli. F. Bariffi: Cattedra di<br />
5,6,8,11,12 Moreover, the time<br />
course of the antitussive effect makes it improbable<br />
that the improvement <strong>in</strong> cough was due only to the<br />
Malattie Respiratorie, Università di Napoli ‘Federico<br />
II’. V. Rocco: Divisione di Fisiopatologia Respiratoria,<br />
Ospedale V. Monaldi, Napoli. G. B. Cavass<strong>in</strong>i: IIa natural resolution of the underly<strong>in</strong>g disease, s<strong>in</strong>ce<br />
relief from cough was already evident with<strong>in</strong> 2–3<br />
days, consider<strong>in</strong>g both quantitative and qualitative<br />
parameters.<br />
Concern<strong>in</strong>g the general safety, results from the<br />
analysis of the vital signs (heart rate and blood pressure)<br />
as well as of the laboratory tests confirm the<br />
good tolerability for both drugs. On the other hand,<br />
significantly less patients (3.6%) compla<strong>in</strong>ed of adverse<br />
events <strong>in</strong> the levodropropiz<strong>in</strong>e group than with dextromethorphan<br />
(12.1%). Extrapolat<strong>in</strong>g these results<br />
to the general population who would use the two<br />
antitussive drugs, the relative risk of adverse events<br />
related to the use of dextromethorphan can be es-<br />
timated to be approximately 3.5 times higher than<br />
with levodropropiz<strong>in</strong>e. This f<strong>in</strong>d<strong>in</strong>g supports a better<br />
Divisione di Medic<strong>in</strong>a Interna, Ospedale Consorziale,<br />
Bentivoglio (BO). E. Far<strong>in</strong>a: Divisione di Pne-<br />
umologia, Ospedale San Salvatore, L’Aquila. E.<br />
Marchi: Centro per lo Studio delle Broncopneumopatie<br />
Senili, Casatenovo (LC). A. Ciaccia:<br />
Cl<strong>in</strong>ica di Malattie dell’Apparato Respiratorio, Po-<br />
licl<strong>in</strong>ico S. Anna, Ferrara. P. Sp<strong>in</strong>a: Divisione di<br />
Medic<strong>in</strong>a Generale, Ospedale Civile, Poggio Rusco<br />
(MN). R. Zu<strong>in</strong>: Istituto di Pneumologia, Università<br />
di Padova. A. Mezzasalma: Divisione di Oto-<br />
r<strong>in</strong>olar<strong>in</strong>goiatria, Ospedale Maggiore, Modica (RG).<br />
F. Foresti: Divisione di Medic<strong>in</strong>a Generale, Ospedale<br />
Civile, Vittoria (RG). G. D’Addetta: Divisione di Medic<strong>in</strong>a,<br />
Ospedale Civile, Monte S. Angelo (FG). G.<br />
Catt<strong>in</strong>i: Divisione di Pneumologia, Ospedale Bellaria,<br />
Bologna. F. Sisti: Divisione di Pneumologia, Presidio<br />
safety profile for levodropropiz<strong>in</strong>e than for de-<br />
Ospedaliero Multizonale ‘D. Cotugno’, Bari.<br />
xtromethorphan, particularly as far as central side<br />
effects are concerned, tak<strong>in</strong>g <strong>in</strong>to account that somnolence<br />
was by far the most frequent adverse event<br />
reported.<br />
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