Montelukast with desloratadine or levocetirizine

for the treatment of persistent allergic rhinitis

Maciej Ciebiada, MD*; Małgorzata Górska-Ciebiada, MD*; Lawrence M. DuBuske, MD†; and
Paweł Górski, MD, PhD*

Background: Montelukast sodium is approved as a treatment for intermittent and persistent allergic rhinitis (AR), but it has
not been evaluated as combined therapy with antihistamines for persistent AR.
Objective: To investigate the effects of 6 weeks of treatment of persistent AR with desloratadine, levocetirizine, or
montelukast alone or in combination.
Methods: A randomized, double-blind, placebo-controlled crossover study was performed. Patients were assigned to 2 arms:
20 received montelukast, 10 mg/d, desloratadine, 5 mg/d, or both or placebo and 20 received montelukast, levocetirizine, or both,
5 mg/d, or placebo. The treatment periods were separated by 2-week washout periods. Symptom scoring, skin prick tests,
spirometry, rhinometry, and nasal lavage were performed the day before and the last days of the treatment periods. Eosinophil
cationic protein levels were evaluated by means of nasal lavage.
Results: The mean ⫾ SD total baseline nasal symptom score was 7.7 ⫾ 0.49 before treatment, 3.74 ⫾ 0.54 after desloratadine
use, 3.6 ⫾ 0.48 after montelukast use, and 3.04 ⫾ 0.4 after montelukast-desloratadine use. The mean ⫾ SD baseline nasal
symptom score was 7.95 ⫾ 0.68 before treatment, 3.02 ⫾ 0.64 after levocetirizine use, 3.44 ⫾ 0.55 after montelukast use, and
2.14 ⫾ 0.39 after montelukast-levocetirizine use. The greatest improvement in nasal symptoms occurred after combination
treatment. Decreases in the level of eosinophil cationic protein were greater after the combined use of montelukast and
antihistamine than after each agent given alone.
Conclusions: For persistent AR, the combination of montelukast and either desloratadine or levocetirizine is more effective
than monotherapy with these agents.
Ann Allergy Asthma Immunol. 2006;97:664–671.

INTRODUCTION Chen et al15 evaluated the effectiveness of montelukast in the

Leukotrienes and histamine have key functions in allergic
inflammation. Leukotrienes can induce bronchoconstriction,1
increase microvascular permeability with edema formation,2
increase mucous secretion,3 and increase inflammatory cell
recruitment.4 – 6 The pathway of leukotriene synthesis may not
be affected by corticosteroids,7,8 potentially resulting in bron-
chospasm in asthmatic patients or nasal congestion in patients
with persistent allergic rhinitis (AR) consequent to leukotri-
enes despite glucocorticosteroid therapy. Thus, leukotrienes
are an important target for allergic disease therapy using
leukotriene receptor antagonists, including montelukast so-
dium, zafirlukast, and pranlukast.
Meltzer et al9 used montelukast either alone or combined
with the antihistamine loratadine as a novel treatment for
seasonal AR. Kurowski et al10 proposed montelukast com-
bined with cetirizine hydrochloride for the prophylactic treat-
ment of seasonal rhinitis. Several trials9,11–13 have evaluated
the efficacy of antileukotrienes alone or combined with an-
tihistamines in the treatment of seasonal AR. Patel et al14 and
* Department of Pneumology and Allergy, Medical University of Lodz,
Lodz, Poland.
† Immunology Research Institute of New England, Gardner, Massachusetts.
Received for publication April 8, 2006.
Accepted for publication in revised form June 4, 2006.
treatment of perennial AR.
METHODS
Patients
Forty patients (age range, 18 – 65 years; mean ⫾ SD age,
28.9 ⫾ 2.7 years; 30 women and 10 men) with persistent AR
were included in this study. Allergic rhinitis was defined
according to Allergic Rhinitis and Its Impact on Asthma
guidelines, where persistent means that the symptoms are
present “more than 4 days a week and for more than 4
weeks.”16 The following inclusion criteria were used to select
individuals for the study: age 18 to 65 years, persistent AR
for at least 2 years, a nasal congestion score of at least 2 using
a 4-point scale (0 ⫽ none and 3 ⫽ severe), and sensitization
to perennial allergens relevant to Central Europe (house dust
mite, cat, and dog) confirmed by a positive skin prick test
result. The exclusion criteria were concomitant sensitization
to seasonal allergens (grass, trees, and weed pollen), bron-
chial asthma, current smoking, respiratory tract infection
during the 6 weeks preceding the study, pregnancy, breast-
feeding, severe illnesses, nasal septal deviation, nasal polyps,
acute or chronic rhinosinusitis, and any other abnormality
that might affect nasal breathing or nocturnal sleep patterns.
Patients were not allowed to use any antiallergic medications
during the study except the study medication. No participant
underwent allergen-specific immunotherapy.

664 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

Study Design
This study was designed as a randomized, double-blind,
placebo-controlled crossover trial using 2 arms. The study
protocol was approved by the local ethical board of the
Medical University of Lodz. All the patients signed an in-
formed consent form agreeing to participate in the study.
Patients were recruited for 4 months (June-September) and
then studied for 7 months (September-March). The study
included four 6-week treatment periods. The treatment peri-
ods were separated by 2-week washout periods.
After a 2-week run-in period, the baseline symptom ques-
tionnaire was administered, and physical evaluations and skin
prick tests were performed. All the patients underwent spi-
rometry, acoustic rhinometry, anterior rhinoscopy, nasal la-
vage, and blood sampling. Eligible patients were randomly
assigned to the group receiving montelukast alone, deslora-
tadine alone, both agents, or placebo (20 patients) or to the
group receiving montelukast alone, levocetirizine alone, both
agents, or placebo (20 patients). The sequence of treatment
was randomly assigned.
After each 6-week treatment period, symptom diary cards,
study medication use, concomitant medication use, and ad-
verse events were evaluated during a study visit in which
clinical assessments and concomitant investigations were re-
peated. Montelukast sodium (Singulair; Merck & Co Inc,
Whitehouse Station, NJ) (10-mg daily dose), desloratadine
(Aerius; Schering Canada Inc, Pointe-Claire, Quebec) (5-mg
daily dose), levocetirizine (Xyzal; UCB, Brussels, Belgium)
(5-mg daily dose), or placebo were used as daily treatment
during the study. Medications were prepared by the hospital
pharmacy staff, who placed the pills in identical white cap-
sules. The medication was administered once daily before
sleep.
Efficacy End Points
Efficacy assessments. The primary end point was the daytime
nasal symptom score, including nasal congestion, sneezing,
itching, and discharge. Nasal congestion was also objectively
measured using acoustic rhinometry. Secondary end points
included the physician global evaluation, daytime eye symp-
tom score, total symptom score, and eosinophil cationic pro-
tein (ECP) concentration in the nasal lavage fluid.
Physician global evaluation. The physician’s global eval-
uation was based on the patient history and the physical
examination, without reference to the patient’s daily diaries.
Symptom scores and drug use. Individual nasal symptom
scores, daytime nasal symptom scores, and daytime eye
symptom scores were recorded. Symptom scores were noted
by each patient before treatment (baseline) and then every
day during the first week and on days 14, 21, 28, 35, and 42
of the treatment period. Symptom scores were graded accord-
ing to the following 4-point severity scale: 0, none; 1, mild
(noticeable but not bothersome); 2, moderate (noticeable and
some of the time bothersome); and 3, severe (bothersome
most of the time/very bothersome some of the time).17 Intake
of drugs was recorded as the number of pills ingested per day.
VOLUME 97, NOVEMBER, 2006
Nasal symptom score. Scores for 4 individual symptoms
(congestion, rhinorrhea, nasal itching, and sneezing) were
noted separately
Total daytime nasal symptom score. The sum of the 4
individual score constituted the total daytime nasal symptom
score; the maximum total nasal symptom score was 12.17
Daytime eye symptom score. Scores for 4 individual symp-
toms (itching, redness, tearing, and puffy eyes) were noted
separately. The daytime eye symptom score was the sum of
the 4 individual scores.17
Nasal blockage monitoring. Acoustic rhinometry was per-
formed to evaluate nasal congestion in an objective and
quantitative manner, as described by Hilberg.18 Patients per-
formed acoustic rhinometry (Rhino Scan 2000; Rhinometrics,
Assens, Denmark) at the first randomization visit and at the
final visit of each 6-week treatment period. On each occasion,
rhinometry was performed in both nostrils before and 15
minutes after intranasal application of 2 puffs of decongestant
(0.1% xylomethasoline). The minimal cross-sectional area
(MCA) of the nasal cavities was measured at the head of the
inferior turbinate of both nostrils and is expressed as the mean
MCA of both nostrils.
Anterior rhinoscopy. Otorhinolaryngologic examination
using an optical method for evaluation of nasal cavity mor-
phologic features and patency was performed before the
study, at the randomization visit. The chondrocostal structure
was evaluated, with morphologic features of the nasal mu-
cous membrane being described with respect to color, edema,
redness, and discharge.
Monitoring of variables of inflammation (mediator as-
says). Nasal lavage was performed according to the method
of Greiff et al.19 Patients were asked to sit with their head
flexed to the chest. Five milliliters of 0.9% sodium chloride
at room temperature was instilled from a syringe connected to
a gum cup into 1 nostril. The patient was instructed not to
breathe through the nose, move, or swallow and to keep the
syringe with cup connected in the nostril. After 5 minutes of
intranasal incubation the sample was drawn back into the
syringe. The procedure was repeated in the opposite nostril.
The sample was centrifuged (1,000 rpm for 10 minutes), and
the supernatant was collected and frozen (⫺70°C) for later
analyses.
Nasal lavage. Lavage fluid ECP concentration was mea-
sured using a sandwich immunoassay (UniCAP; Pharmacia
Diagnostics, Uppsala, Sweden), with a standard assay range
of 2 to 200 ␮g/L.
Spirometry and skin prick tests. Spirometry was performed
at the randomization visit using a computer-assisted spirom-
eter (Lung Test 1000; MES Dymek, D’browski SA, Cracov,
Poland) according to standardized guidelines.20 Reference
values of the European Community for Coal and Steel were
used.20 Values are expressed as a percentage of the predicted
values. Skin prick tests with common allergens (Allergop-
harma, Reinbeck, Germany) were performed for each patient
1 day before the study.
665
Statistical Methods
Statistical analysis was performed using Kruskal-Wallis anal-
ysis of variance, the Mann-Whitney U test, and the Wilcoxon
test.
RESULTS
Forty of 350 screened patients were randomized. The pres-
ence of concomitant sensitization to seasonal aeroallergens
was the most common reason for patient exclusion from the
study. The baseline characteristics of patients who completed
the study are given in Table 1.
There were 2 patient withdrawals before completion of the
study, both noted on the last visit. There were no early study
discontinuations during visits 1 to 9, and there were no
discontinuations because of adverse events. The reason for
the study discontinuation was relocation out of the area and
job change. All the patients were allergic to house dust mite,
and 6 patients were also sensitized to cat and dog allergens.
Two patients were sensitized to all the perennial allergens
used in the skin prick tests. None of the patients had asthma,
nasal septal deviation, or nasal polyps.
Treatment With Desloratadine, Levocetirizine, or
Montelukast Alone
Symptom scores. Monotherapy with desloratadine, levoceti-
rizine, and montelukast improved symptom scores for the
primary and secondary end points. Compared with baseline
(no treatment), montelukast (in both groups), desloratadine,
or levocetirizine alone significantly improved daytime nasal
symptom scores (itching, sneezing, discharge, and congestion
scores), daytime eye symptom scores, and total symptom
scores.
Daily nasal symptoms score. Montelukast was signifi-
cantly more effective than placebo in improving each of the
individual nasal symptoms in the daily nasal symptom score
in both arms of the study except for nasal discharge in the
montelukast-levocetirizine arm (comparison of itching scores
gave P ⫽ .03, with others being P ⬍ .001 for montelukast vs
placebo in both study arms) (Table 2).
In general, the antihistamines were comparable with mon-
telukast in improving scores for individual nasal symptoms.
However, montelukast was slightly more effective than
desloratadine in reducing sneezing, nasal discharge, and nasal
blockage (Fig 1 and Table 2).
Daytime eye symptom score. Montelukast improved day-
time eye symptom scores compared with baseline (P ⬍ .001).
The effectiveness of montelukast on daytime eye symptom
scores was comparable with desloratadine in the montelukast-
Table 1. Baseline Characteristics of the 40 Study Patients
Montelukast-levocetirizine
Characteristics
Sex, F:M, No.
Age, mean ⫾ SEM, y
Duration of persistent allergic rhinitis, mean ⫾ SEM, y
666
desloratadine arm and with placebo in the montelukast-levo-
cetirizine arm (Table 2).
Total daytime nasal symptom scores. Improvement in the
total nasal symptom score was observed in patients treated
with montelukast alone, desloratadine alone, or levocetirizine
alone compared with treatment with placebo. Patients treated
with montelukast demonstrated greater improvement than
those treated with desloratadine in the montelukast-deslora-
tadine arm (P ⫽ .02, montelukast vs desloratadine). In the
montelukast-levocetirizine arm, levocetirizine produced
greater improvement than montelukast (P ⫽ .03, levocetiriz-
ine vs montelukast) (Fig 2 and Table 2).
Mediator Assays
Levocetirizine, desloratadine, and montelukast in both arms
of the study significantly reduced concentrations of ECP in
nasal lavage fluid compared with baseline (P ⬍ .001) and
placebo. Compared with desloratadine, montelukast caused a
greater decrease in lavage concentration of ECP in the mon-
telukast-desloratadine arm (P ⫽ .02, montelukast vs deslora-
tadine). In the montelukast-levocetirizine arm, montelukast
provided no significant benefit compared with levocetirizine
(Fig 3 and Table 2).
Acoustic Rhinometry
In the montelukast-levocetirizine study arm, treatment with
montelukast alone resulted in a significant increase of the
mean MCA of the nasal cavity compared with the mean MCA
of the nasal cavity after levocetirizine use (P ⫽ .04), after
placebo use (P ⫽ .01), or at baseline (P ⬍ .001). The effect
of treatment with levocetirizine was comparable with that of
placebo. In the montelukast-desloratadine arm, either monte-
lukast alone or desloratadine alone significantly improved the
mean MCA compared with baseline (P ⫽ .01 for deslorata-
dine vs baseline and P ⫽ .006 for montelukast vs baseline)
(Table 2).
Combination Treatment (Montelukast-Levocetirizine or
Montelukast-Desloratadine)
Compared with baseline and placebo, montelukast-deslorata-
dine combination treatment and montelukast-levocetirizine
combination treatment significantly improved daytime nasal
symptom scores (itching, sneezing, nasal discharge, and nasal
congestion) (Fig 1 and Table 2) and also daytime eye symp-
tom scores and total symptom scores (comparison of itching
scores in the montelukast-levocetirizine arm gave P ⫽ .002
vs placebo, other symptom scores P ⬍ .001 for combination
treatment vs baseline and placebo).
Montelukast-desloratadine
arm (n ⴝ 20) arm (n ⴝ 20)
14:6 16:4
23.65 ⫾ 2.1 34.1 ⫾ 2.69
5.65 ⫾ 0.85 7.85 ⫾ 1.32
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
Table 2. Symptom Scores, ECP Concentrations in Nasal Lavage Fluid, and Acoustic Rhinometry Values at Baseline and After 6 Weeks of
Treatmenta
Montelukast-levocetirizine arm (n ⴝ 20) Montelukast-desloratadine arm (n ⴝ 20)
Sneezing Discharge Itching Congestion Sneezing Discharge Itching Congestion
Nasal symptom score
Baseline 1.95 ⫾ 0.21 2.05 ⫾ 0.25 1.4 ⫾ 0.27 2.55 ⫾ 0.11 1.85 ⫾ 0.2 2.1 ⫾ 0.17 1.45 ⫾ 0.23 2.3 ⫾ 0.1
Placebo 1.36 ⫾ 0.24b 1.38 ⫾ 0.23b 0.71 ⫾ 0.21b 1.55 ⫾ 0.24 1.36 ⫾ 0.22c,d 1.66 ⫾ 0.21c 0.8 ⫾ 0.22b 1.91 ⫾ 0.2
Antihistamine 0.67 ⫾ 0.21b,d 0.97 ⫾ 0.23b,d 0.38 ⫾ 0.17b,e 1 ⫾ 0.19 0.98 ⫾ 0.18b,d 1.04 ⫾ 0.22b,d 0.43 ⫾ 0.16b,f 1.3 ⫾ 0.23
Montelukast 0.81 ⫾ 0.2b,d 1.16 ⫾ 0.21b 0.39 ⫾ 0.15b,e 1.09 ⫾ 0.2 0.89 ⫾ 0.16b,d 0.96 ⫾ 0.2b,d 0.49 ⫾ 0.15b,d 1.26 ⫾ 0.18
Montelukast ⫹ 0.44 ⫾ 0.15b,d,g 0.74 ⫾ 0.16b,d,h 0.21 ⫾ 0.1b,f 0.76 ⫾ 0.16 0.74 ⫾ 0.14b,d,i 0.96 ⫾ 0.18b,d 0.32 ⫾ 0.12b,d 1.03 ⫾ 0.17
antihistamine
Total daytime nasal
symptom score
Baseline 7.95 ⫾ 0.68 7.7 ⫾ 0.49
Placebo 4.99 ⫾ 0.76 5.73 ⫾ 0.6
Antihistamine 3.02 ⫾ 0.64 3.74 ⫾ 0.54
Montelukast 3.44 ⫾ 0.55 3.6 ⫾ 0.48
Montelukast ⫹ 2.14 ⫾ 0.39 3.04 ⫾ 0.4
antihistamine
Daytime eye symptom
score
Baseline 3.15 ⫾ 0.73 4.85 ⫾ 0.87
Placebo 1.71 ⫾ 0.62b 2.92 ⫾ 0.78b
Antihistamine 0.48 ⫾ 0.26b,d,h 1.61 ⫾ 0.45b,f
Montelukast 1.13 ⫾ 0.38b 1.51 ⫾ 0.49b,d
Montelukast ⫹ 0.46 ⫾ 0.22b,d,h 1.09 ⫾ 0.4b,d,i
antihistamine
Nasal lavage ECP
concentration, ␮ g/L
Baseline 10.18 ⫾ 1.35 13.54 ⫾ 1.24
Placebo 10.02 ⫾ 1.49 10.99 ⫾ 1.15
Antihistamine 4.46 ⫾ 0.6 7.46 ⫾ 0.94
Montelukast 3.66 ⫾ 0.73 4.59 ⫾ 0.54
Montelukast ⫹ 3.89 ⫾ 0.61 3.17 ⫾ 0.46
antihistamine
Minimal cross-sectional
area, cm2
Baseline 0.76 ⫾ 0.03 0.78 ⫾ 0.03
Placebo 0.82 ⫾ 0.05 0.82 ⫾ 0.05
Antihistamine 0.8 ⫾ 0.04 0.88 ⫾ 0.05k
Montelukast 1.02 ⫾ 0.06b,e,i 0.94 ⫾ 0.07c
Montelukast ⫹ 1.02 ⫾ 0.05b,f,j 0.95 ⫾ 0.06c
antihistamine
Abbreviation: ECP, eosinophil cationic protein.
a
Data are expressed as mean ⫾ SEM at baseline and after the 6-week treatment periods. For P values for congestion, see Figure 2; total nasal
symptom scores, see Figure 1; and lavage ECP concentrations, see Figure 3.
b
P ⬍ .001 vs baseline.
c
P ⬍ .01 vs baseline.
d
P ⬍ .001 vs placebo.
e
P ⬍ .05 vs placebo.
f
P ⬍ .01 vs placebo.
g
P ⬍ .01 vs montelukast.
h
P ⬍ .001 vs montelukast.
i
P ⬍ .05 vs desloratadine.
j
P ⬍ .01 vs levocetirizine.
k
P ⬍ .05 vs baseline.

VOLUME 97, NOVEMBER, 2006 667

 Figure 1. Mean congestion scores after 6 weeks of treatment with montelukast alone, levocetirizine alone, or the combination (A) or with montelukast alone,
desloratadine alone, or the combination (B). *P ⬍ .001 vs baseline. †P ⬍ .001 vs placebo. ‡P ⬍ .01 vs montelukast. §P ⬍ .01 vs baseline. ¶P ⬍ .05 vs
desloratadine. 储P ⬍ .05 vs montelukast. Error bars represent SEM.

Figure 2. Mean total nasal symptom scores after 6 weeks of treatment with montelukast alone, levocetirizine alone, or the combination (A) or with montelukast
alone, desloratadine alone, or the combination (B). *P ⬍ .001 vs baseline. †P ⬍ .001 vs placebo. ‡P ⬍ .05 vs montelukast. §P ⬍ .001 vs montelukast. ¶P ⬍
.05 vs placebo. 储P ⬍ .05 vs desloratadine. #P ⬍ .001 vs desloratadine. Error bars represent SEM.

Compared with monotherapy with montelukast, combina-
tion therapy with montelukast-levocetirizine resulted in a
significantly greater improvement in total nasal symptom
scores (P ⬍ .001 for combination therapy vs montelukast
alone) and daytime eye symptom scores (P ⬍ .001 for com-
bination therapy vs montelukast alone). Compared with treat-
ment with montelukast alone, montelukast-levocetirizine
combination therapy resulted in less congestion (P ⫽ .002),
less sneezing (P ⫽ .001), and less discharge from the nose
(P ⬍ .001). There was no significant difference in itching
scores between montelukast alone and combination therapy.
Combination therapy had no significant benefit over treat-
ment with levocetirizine alone for all individual nasal symp-
tom scores in the study (Table 2).
In the montelukast-desloratadine arm, combination treat-
ment produced significant improvements in individual nasal
symptom scores, including congestion (P ⫽ .03 vs deslora-
tadine alone and P ⫽ .01 vs montelukast alone). Combination
therapy improved the total nasal symptom score compared
with desloratadine alone (P ⬍ .001) or montelukast alone
(P ⫽ .03) and the daytime eye symptoms score (P ⫽ .02 vs
desloratadine alone). Combination treatment gave no signif-
icant improvement vs monotherapy for discharge from the
nose and itching. Combination therapy was not more effec-
tive than montelukast alone in improving sneezing scores
(Table 2).
Mediator Assays
There was a significant decrease of ECP concentration in
nasal lavage after montelukast-desloratadine or montelukast-
levocetirizine combination treatment compared with ECP
baseline levels (P ⬍ .001 in both arms) or after placebo
administration (P ⬍ .001 in both arms). In addition, combi-
nation treatment was more effective in reducing ECP con-
centrations than treatment with antihistamine alone (P ⬍ .001
in the montelukast-desloratadine arm and P ⫽ .02 in the
montelukast-levocetirizine arm). Combination therapy was
also more effective in reducing nasal ECP levels than mon-

668 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY

 Figure 3. Mean nasal lavage fluid eosinophil cationic protein (ECP) concentrations after 6 weeks of treatment with montelukast alone, levocetirizine alone,
or the combination (A) or with montelukast alone, desloratadine alone, or the combination (B). *P ⬍ .001 vs baseline. †P ⬍ .05 vs placebo. ‡P ⬍ .001 vs placebo.
§P ⬍ .05 vs levocetirizine. ¶P ⬍ .05 vs desloratadine. 储P ⬍ .001 vs desloratadine. #P ⬍ .05 vs montelukast. Error bars represent SEM.
telukast alone in the montelukast-desloratadine arm (P ⫽
.03). In the montelukast-levocetirizine arm, there was no
additional effect on ECP concentration after combination
therapy compared with montelukast monotherapy (Fig 3).
Acoustic Rhinometry
Combination therapy resulted in a significant increase in the
MCA of the nasal cavity compared with baseline (P ⬍ .001
in the montelukast-levocetirizine arm and P ⫽ .004 in the
montelukast-desloratadine arm), placebo (P ⫽ .006 in the
montelukast-levocetirizine arm and P ⫽ .04 in the monte-
lukast-desloratadine arm), and levocetirizine alone (P ⫽
.001) in the montelukast-levocetirizine arm. The MCA values
were similar after combination treatment and monotherapy
with desloratadine in the montelukast-desloratadine arm. In
addition, there was no difference between combination treat-
ment and montelukast monotherapy in both groups (Table 2).
DISCUSSION
Nasal congestion is the dominant symptom of persistent AR.
The presence of nasal congestion was one of the main inclu-
sion criteria in this study. Furthermore, evaluation of nasal
blockage after treatment was one of the primary efficacy end
points in this trial. The mechanism of allergic nasal obstruc-
tion is complex. Blockage is caused by mucosal edema,
infiltration of the mucosa by inflammatory cells, enlargement
of sinusoidal capacitance vessels, rhinorrhea, and increased
mucus production. The early and late phases of the allergic
reaction contribute to nasal obstruction. There is also involve-
ment of histamine, leukotrienes, adhesion molecules, and
inflammatory cells.6
Histamine stimulates blood vessels, nerves, and mucus-
producing glands. It is primarily involved in the early-phase
response and in the induction of sneezing, itching, and rhi-
norrhea. Histamine has an obstructive effect only in relatively
high concentrations.21 In perennial AR, the level of histamine
in nasal lavage is not markedly elevated.
VOLUME 97, NOVEMBER, 2006
Leukotrienes are released mainly by mast cells in the early
phase of allergic response and by basophils, eosinophils, and
neutrophils during the late phase of response. Leukotrienes
are responsible for the induction and maintenance of nasal
blockage, with less effect on other rhinitis symptoms, such as
sneezing and itching.21,22 Leukotrienes increase nasal airway
blood flow, increase vascular permeability, enhance plasma
exudation and airway edema,2 increase mucous secretion,3
reduce ciliary motility, and reduce mucociliary clearance.23
Some leukotrienes (leukotriene D4 and leukotriene E4) are
potent and specific chemoattractants for eosinophils4 and
increase eosinophil numbers in the lamina propria of the
airway mucosa.5
Leukotriene concentrations are elevated in nasal lavage
performed during the early- and late-phase responses after the
allergen challenge in seasonal and perennial AR.24,25 Higashi
et al21 showed that there is a significant correlation between
nasal blockage and urinary leukotriene E4 levels in patients
with seasonal AR.
Persistent AR is characterized predominantly by persistent
congestion. Other symptoms, including sneezing, itching,
rhinorrhea, and eye symptoms, are occasional. Congestion is
initiated and sustained mainly by leukotrienes. Other symp-
toms are triggered mainly by histamine. Histamine has a
relatively minor impact on nasal congestion as evaluated by
H1-mediated events.
Although nasal itching, sneezing, and rhinorrhea are re-
duced by H1 receptor antagonists, nasal blockage is only
partially modified by these medications. Therefore, it is rea-
sonable to consider the addition of the leukotriene receptor
antagonist montelukast for the purpose of nasal blockage
reduction during the treatment of persistent AR.
Available data suggest that leukotriene receptor antago-
nists are safe and effective as standard therapy in asthma26 –28
and intermittent9,11–13,17 and persistent14,15 AR. The cysteinyl
leukotriene type 1 receptor antagonist montelukast, adminis-
669
tered once daily, has been documented to significantly im-
prove asthma symptoms and lung function, reduce asthma
exacerbations, and increase quality of life. Furthermore, it
may allow dose reduction of inhaled corticosteroids in asth-
matic patients.
For seasonal AR, randomized placebo-controlled trials
have revealed different, sometimes contradictory, data. In
some trials, montelukast alone or combined with antihista-
mines improved nasal symptom scores, including conges-
tion,9,11–13,29 with9 or without12,13 improvement of eye symp-
tom scores. Some studies of AR showed greater efficacy of
montelukast and antihistamine as combination treatment
compared with treatment with each agent alone.9,13
The relative efficacy of montelukast alone vs montelukast
combined with antihistamines in the treatment of persistent
AR has not been reported. This pilot study evaluated the
effect of monotherapy with the leukotriene receptor antago-
nist montelukast or the new generation of antihistamines,
desloratadine or levocetirizine, and the combination of these
agents in the treatment of persistent AR. Montelukast as a
single daily dose of 10 mg, desloratadine as a single daily
dose of 5 mg, and levocetirizine as a single daily dose of 5 mg
and montelukast-antihistamine combined therapy provided
improvement compared with baseline (no treatment) in all
primary and secondary end points of this study.
Montelukast alone was significantly more effective than
placebo in improving congestion and other nasal symptoms in
both arms of the study except for discharge from the nose in
the montelukast-levocetirizine arm. Leukotrienes do not sig-
nificantly contribute to sneezing and itching. Therefore, leu-
kotriene receptor antagonists would not be expected to reduce
these symptoms markedly. In this study, montelukast dimin-
ished all the symptoms of persistent AR compared with
baseline. Combined montelukast and antihistamines (deslo-
ratadine or levocetirizine) gave additional, frequently signif-
icant, benefits in the reduction of nasal symptoms.
This is the first study, to our knowledge, to compare the
efficacy of combined therapy with montelukast and antihis-
tamine vs antihistamine alone in patients with persistent AR.
Previous studies by Patel et al14 and Chen et al15 evaluated
and compared only the efficacy of montelukast vs antihista-
mine. In this study, we provide strong evidence that the
combination of montelukast with antihistamines (deslorata-
dine or levocetirizine) gives additional, frequently significant,
benefits in the reduction of nasal symptoms.
REFERENCES
1. Bisgaard H, Groth S, Madsen F. Bronchial hyperreactivity to
leukotriene D4 and histamine in exogenous asthma. BMJ. 1985;
290:1468 –1471.
2. Bisgaard H, Olsson P, Bende M. Effect of leukotriene D4 on
nasal mucosal blood flow, nasal airway resistance and nasal
secretion in humans. Clin Allergy. 1986;16:289 –297.
3. Garcia-Marcos L, Schuster A. New perspectives for asthma
treatment: anti-leukotriene drugs. Pediatr Allergy Immunol.
1999;10:77– 88.
4. Busse WW, Sedgwick JB. Eosinophils in asthma. Ann Allergy.
670
1992;68:286 –290.
5. Laitinen LA, Laitinen A, Haahtela T, et al. Leukotriene E4 and
granulocyte infiltration into asthmatic airways. Lancet. 1993;
341:989 –990.
6. Terada N, Kono A, Togawa K. Biochemical properties of eo-
sinophils and their preferential accumulation mechanism in
nasal allergy. J Allergy Clin Immunol. 1994;94:629 – 642.
7. O’Shaughnessy KM, Wellings R, Gillies B, et al. Differential
effects of fluticasone propionate on allergen evoked broncho-
constriction and increased urinary leukotriene E4 excretion. Am
Rev Respir Dis. 1993;147:1472–1476.
8. Dworski R, Fitzgerald GA, Oates JA, et al. Effect of oral
prednisone on airway inflammatory mediators in atopic asthma.
Am J Respir Crit Care Med. 1994;149:953–959.
9. Meltzer EO, Malmstrom K, Lu S, et al. Concomitant monte-
lukast and loratadine as treatment for seasonal allergic rhinitis:
a randomized, placebo controlled clinical trial. J Allergy Clin
Immunol. 2000;105:917–922.
10. Kurowski M, Kuna P, Gorski P. Montelukast plus cetirizine in
the prophylactic treatment of seasonal allergic rhinitis: influence
on clinical symptoms and nasal allergic inflammation. Allergy.
2004;59:280 –288.
11. Philip G, Malmstrom K, Hampel FC, et al. Montelukast for
treating seasonal allergic rhinitis: a randomized, double blind,
placebo controlled trial performed in the spring. Clin Exp Al-
lergy. 2002;32:1020 –1028.
12. van Adelsberg J, Philip G, LaForce CF, et al. Randomized
controlled trial evaluating the clinical benefit of montelukast for
treating spring seasonal allergic rhinitis. Ann Allergy Asthma
Immunol. 2003;90:214 –222.
13. Nayak AS, Philip G, Lu S, et al. Efficacy and tolerability of
montelukast alone or in combination with loratadine in seasonal
allergic rhinitis: a multicenter, randomized, double blind, pla-
cebo controlled trial performed in the fall. Ann Allergy Asthma
Immunol. 2002;88:592– 600.
14. Patel P, Philip G, Yang W, et al. Randomized, double-blind,
placebo-controlled study of montelukast for treating perennial
allergic rhinitis. Ann Allergy Asthma Immunol. 2005;95:
551–557.
15. Chen ST, Lu KH, Sun HL, et al. Randomized placebo-
controlled trial comparing montelukast and cetirizine for treat-
ing perennial allergic rhinitis in children aged 2– 6 yr. Pediatr
Allergy Immunol. 2006;17:49 –54.
16. Bousquet J, Van Cauwenberge P, Khaltaev N; Workshop Expert
Panel. Allergic Rhinitis and its Impact on Asthma (ARIA). J
Allergy Clin Immunol. 2001;108:S150.
17. Khachikian D, VHA Pharmacy Benefits Management Strategic
Healthcare Group and the Medical Advisory Panel. Use of
montelukast in seasonal allergic rhinitis. Drug Class Rev. 2003;
2:1–10.
18. Hilberg O. Objective measurement of nasal airway dimensions
using acoustic rhinometry: methodological and clinical aspects.
Allergy. 2002;57(suppl 70):5–39.
19. Greiff L, Pipkorn U, Alkner U, et al. The “nasal pool” device
applies controlled concentrations of solutes on human nasal
airway mucosa and samples its surface exudations/secretions.
Clin Exp Allergy. 1990;20:253–259.
20. Quanjer PH, Tammeling GJ, Cotes JE, et al. Standardization of
lung function testing: official statement of the European Respi-
ratory Society. Eur Respir J Suppl. 1993;16:1–100.
21. Higashi N, Taniguchi M, Mita H, et al. Nasal blockage and
ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY
 urinary leukotriene E4 concentration in patients with seasonal
allergic rhinitis. Allergy. 2003;58:476 – 480.
22. Borish L. Allergic rhinitis: systemic inflammation and implica-
tions for management. J Allergy Clin Immunol. 2003;112:
1021–1031.
23. Bisgaard H, Pedersen M. SRS-A leukotrienes decrease the
activity of humanrespiratory cilia. Clin Allergy. 1987;17:
95–103.
24. Knani J, Campbell A, Enander I, et al. Indirect evidence of nasal
inflammation assessed by titration of inflammatory mediators
and enumeration of cells in nasal secretions of patients with
chronic rhinitis. J Allergy Clin Immunol. 1992;90(pt1):
880 – 889.
25. Volovitz B, Osur SL, Bernstein JM, et al. Leukotriene C4
release in upper respiratory mucosa during natural exposure to
ragweed in ragweed-sensitive children. J Allergy Clin Immunol.
1988;82:414 – 418.
26. Reicin A, White R, Weinstein SF, et al. Montelukast, a leuko-
triene receptor antagonist, in combination with loratadine, a
histamine receptor antagonist, in the treatment of chronic
asthma. Arch Intern Med. 2000;160:2481–2488.
27. Rouquet A, Dahlen B, Kumulin M, et al. Combined antagonism
of leukotrienes and histamine produces predominant inhibition
of allergen-induced early and late phase airway obstruction in
asthmatics. Am J Respir Crit Care Med. 1997;155:1856 –1863.
28. Altman LC, Munk Z, Seltzer J, et al. A placebo controlled, dose
ranging study of montelukast, a cysteinyl leukotriene-receptor
antagonist. J Allergy Clin Immunol. 1998;102:50 –56.
29. Pullerits T, Praks L, Ristioja V, et al. Comparison of nasal
glucocorticoid, antileukotriene, and a combination of antileu-
kotriene and antihistamine in the treatment of seasonal allergic
rhinitis. J Allergy Clin Immunol. 2002;109:949 –955.
Requests for reprints should be addressed to:
Paweł Górski, MD, PhD
Department of Pneumology and Allergy
Medical University of Lodz
Kopcinskego Street 22
90-153 Lodz, Poland
E-mail: p_gorski@toya.net.pl

Answers to CME examination—Annals of Allergy,

Asthma & Immunology, November 2006 Santos CB et al:
Allergic rhinitis and its effect on sleep, fatigue, and daytime
somnolence. Ann Allergy Asthma Immunol. 2006;97:579 –
587.
1. c
2. a
3. a
4. d
5. e
6. b
7. d

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