INTRODUCTION
Montelukast is one of the widely used leukotriene receptor antagonists,
which can alleviate the symptoms of allergic diseases, such as asthma
and allergic rhinitis, and improve the prognosis of patients by reducing
the production of inflammatory
mediators.1-3Montelukast can be used in adults and
children. However, with its widespread use, the occurrence of
neuropsychiatric events (NEs) in patients taking montelukast increases
significantly.4-14
Considering the pharmacovigilance
studies4-6,8,11-14and case
reports7,9,10of neuropsychiatric adverse reactions,
the US Food and Drug Administration (FDA) adds a warning for NEs to the
montelukast label. Before using montelukast, patient’s condition should
be considered comprehensively, considering whether the patient has
depression, headache, anxiety, insomnia, aggression, suicidal ideation,
or behavioral neuropsychiatric adverse
reactions.15,16However, these warnings are not taken
seriously, and the mental state of the patient is not considered when
the montelukast envoy is present. In 2020, the FDA has issued the
following black box warning: limit the use of allergic rhinitis unless
the patient is ineffective or unable to tolerate other clinical drugs
and asthma patients should be fully considered before using
montelukast.17
However, conflicting research has been found on the relationship between
NEs and montelukast. Studies have shown that patients who use
montelukast have a high occurrence of NEs, whereas others have found
that the occurrence of NEs is not related to the use of
montelukast.4-14No statistical analysis was found on
the relationship between NEs and montelukast.18As
such, the purpose of this article is to illustrate the relationship
between NEs and montelukast through high-quality randomized controlled
study results.
METHODS
Search strategy
We conducted a comprehensive survey of patients with allergic rhinitis
and/or asthma who used montelukast to analyze the possibility of NEs.
MEDLINE (1966 to March 2020), Embase (1974 to March 2020), Web of
Science databases, and reference lists of the retrieved studies were
used. The search formula used was as follows: montelukast and
drug-related side effects and adverse reactions.
Inclusion criteria and trial selection
Studies were included if they met the following criteria: (i)
montelukast was used to treat patients with allergic rhinitis and/or
asthma; (ii) randomized controlled trials; (iii) full text could be
found online and published in English language; (iiii) the study
provided available data for analysis. The selection process of included
studies was shown in the flow chart (Figure 1).
Quality assessment
The quality of the included studies was assessed by Jadad
scale.19Each study can be assessed by methods (method
of patient random allocation, concealment of allocation, blinding and
data loss to follow). Afterward, the Cochrane Handbook for Systematic
Reviews of Interventions v.5.1.0.20was used to grade
individual studies. Each study was assigned a category: A, low risk of
bias where the study met almost the criteria; B, moderate risk of bias
where the study met part or unclear for one or more quality criteria; C,
high risk of bias where the study did not meet or included the criteria.
Differences were resolved by discussion among the authors.
Data extraction
The measurable data were collected from the included study: (1) first
author name, (2) publication year, (3) name of disease and type of
design, (4) the sample number and patients’ age, (5) the therapy that
the patients in the experimental group received, (7) the sample number
of NE occurrence and the type of NEs, (8) follow-up period.
Statistical analysis
The STATA 12.0 package (StataCorp, College Station, TX, USA) was used to
analyze the data. Fixed or random-effect models will be used to combine
statistics. The relative risk (RR) was used to estimate dichotomous
outcomes and the 95% confidence interval (CI). I2 test and x2-based Q
statistics were used to assess the heterogeneity of the study. If I2
value >50% or p-value <0.1, then the
heterogeneity of the study was significant, and the fixed-effect model
was used to analyze the study. Otherwise, the random-effect model was
used. If p-value was less than 0.05, then the result was considered
statistically significant.
RESULTS
Characteristics of individual studies
We found 574 articles in the database and reference lists. After
eliminating duplicate articles, 460 articles were included for further
analysis. Based on reading of title and abstract, 418 articles were
excluded. Finally, we selected 13
articles1,21-32containing 16 RCTs for meta-analysis
after reading the full text. The screening process and the
characteristics of each included study are shown in Figure 1 and Table
1, respectively.
Quality of individual studies
All studies were randomized controlled studies and calculation of sample
size. Three studies22,31,32containing four RCTs did
not explain the random method, and one study did not explain the blind
method; Jadad scores were rating B. One
study32containing two RCTs were rating C without
blinding. Five studies24,25,28,31,32containing seven
RCTs did not used intention-to-treat analysis. Consequently, the quality
level of two RCTs of one study was C, and the quality level of three
studies22,28,31was B; the rest of the studies21,23-25,27,28containing RCTs with Jadad scores were
A. (Table 2). Bruce et al.32reported that the Jadad
level was C, which indicated a high risk in the study and might cause a
bias to the results if included in the meta-analysis. Therefore, we did
not include this study in the following analysis.
NE
3.31 The occurrence of NEs in a randomized placebo-controlled study
Ten
RCTs1,21-27,29,31that enrolled 3721 patients
(2262
in
the
montelukast group and 1459 in the placebo group)
were
used to access the occurrence of NEs
in patients with allergic rhinitis and/or asthma. No
significant
heterogeneity (I2<50%, P>0.1) was found in our
research. Therefore, we used the fixed-effect model to consolidate the
statistics, and risk ratio (RR) was used to assess the size of the
effect (Figure 2A). The forest plot showed no statistical significance
(RR=0.88, 95%CI=0.74–1.06, P=0.18>0.05) between the NEs
in the experimental and control groups. This finding indicated that the
use of montelukast did not increase the incidence of NEs in patients
with allergic rhinitis and/or asthma. We developed a funnel plot to
assess the publication bias of NEs in patients receiving montelukast or
placebo, which presented a symmetrical appearance and was not
statistically significant (Begg test, P=0.86; Egger test, P=0.67),
showing a low publication bias (Figure 2B).
3.32 Headache-related NEs
Nine RCTs1,21-27,31that enrolled 3393 patients (2098
in the montelukast group and 1295 in the placebo group) were used to
access the occurrence of headache, the most common event in NEs. No
significant heterogeneity was found; thus, we used the fixed-effect
model (RR=0.87, 95%CI=0.71–1.06, P=0.177>0.05; Figure 3).
The result indicated that no statistical significance was found between
the montelukast group and placebo group for the occurrence of headache.
3.33 NEs in patients with asthma or AR
Asthma and AR were the common chronic inflammatory diseases. Six
RCTs21-24,27,29that enrolled 2115 patients (1331 in
the montelukast group and 784 in the placebo group) included data on the
occurrence of NEs in asthma patients. The study indicated that no
statistically significant difference was found between the montelukast
group and placebo group (RR=0.86, 95%CI=0.713–1.05, P =0.13;
Figure 4A). Three RCTs25,26,31 evaluated the adverse
reactions of montelukast in 993 AR patients (620 in the montelukast
group and 373 in the placebo group). This result suggested that no
increase in NEs in patients with allergic rhinitis who received
montelukast compared with the placebo group (RR=1.04, 95%CI=0.55–1.98,P =0.91; Figure 4B).
3.34 NE in children or adults
Eight RCTs1,22-27,29that enrolled adult 2972 patients
(1781 in the montelukast group and 1191 in the placebo group) were used
to estimate the occurrence of NE. The forest plots of the fixed-effect
model indicated a RR of 0.87 and 95%CI of 0.71 to 1.06 (P =0.16;
Figure 5A). No statistically significant difference was found in the two
groups. Two RCTs with 749 child patients evaluated the occurrence of NEs
(481 in the montelukast group and 268 in the placebo group). Based on
the fixed-effect model, the
result
showed the number of NE without increase in child patients taking
montelukast compared with placebo (RR=0.97, 95%CI=0.64–1.5,P =0.9; Figure 5B).
3.35 Relationship between NE and montelukast or common clinical drugs
Four RCTs25,26,28,30that enrolled 875 patients (437 in
the experimental group and 436 in the control group) were used to access
the occurrence of NE in patients with allergic rhinitis and/or asthma.
We made a funnel plot to evaluate publication bias. A symmetrical
appearance indicated a low publication bias (Begg test, P =0.73;
Egger test, P =0.75; Figure 6A). Two
RCTs23,24were used to compare the NEs in patients
taking budesonide with patients taking montelukast. No heterogeneity was
found (I2<50%). Thus, a
fixed-effect
model was used. This result showed no statistically significant
difference (RR=4.0, 95%CI=0.47–34, P =0.21; Figure 6B). The
remaining two RCTs with 785 patients (392 in the experimental group and
393 in the control group) were used to compare the incidence of NEs in
patients taking loratadine with that taking montelukast. The
heterogeneity test result was
I2=60.7%>50%,P >0.1. A random-effect model was used to combine the
effect; RR was 0.39, and 95%CI was 0.07 to 2.18 (P =0.29; Figure
6C). Furthermore, montelukast combined with loratadine likely have an NE
than loratadine.
DISCUSSION
Asthma and allergic rhinitis are common allergic diseases with high
occurrence. Clinically, montelukast is used in the treatment of asthma
and allergic rhinitis. 33,34Montelukast was approved
by the FDA in 1998 for the treatment of asthma and in 2002 for the
treatment of allergic rhinitis, but long-term use of montelukast could
cause neuropsychiatric adverse reactions.33FDA added
NEs to adverse drug reactions in 2009, and with the increase in reports
of NEs, FDA strengthened existing warnings about serious behavior and
mood-related changes with montelukast on March 4,
2020.15-17
However, only pharmacovigilance studies4-6,8,11-14and
case reports7,9,10 have shown the relationship that montelukast could
cause neuropsychiatric adverse reactions. High-quality randomized
controlled studies have not been comprehensively analyzed. Therefore,
the purpose of this meta-analysis is to compare whether the use of
montelukast could cause NEs in patients with asthma, rhinitis, or both.
Ten articles 1,21-26,29,31 and 3721 participants were
included in our meta-analysis. The results indicated no statistical
significance (RR=0.88, 95%CI=0.74–1.06, P=0.18>0.05).
This phenomenon could be related to the type of disease; thus, we
grouped the disease type to further study. Six randomized controlled
studies21-24,27,29of asthma with 2115 patients were
used. The results showed no significant difference between the
montelukast group and placebo group (RR=0.86, 95%CI=0.713–1.05,
p=0.13). Three randomized controlled studies24,25,29of allergic rhinitis involving 993 patients
were used, and the fixed-effect model combined with statistics showed
that montelukast use did not lead to a significant increase in adverse
events (RR=1.04, 95%CI=0.55–1.98, P=0.91). We suggest that disease
type does not have a significant correlation to montelukast and NEs. In
addition, the most common neuropsychiatric adverse reaction, namely,
“headache,” was analyzed. Nine randomized controlled
studies1,21-27,31involving 3393 patients were used, of
which 2098 were in the montelukast group, and the rest were in the
placebo group. The analysis showed that montelukast did not cause a
significant increase in the incidence of headache. The results of the
most common clinical NE, namely, “headache,” were consistent with the
overall results of the included study.
Aldea-Perona et al5found age differences in the
occurrence of NEs, and neuropsychiatric diseases were more common in
children than in adults. As such, we conducted age grouping to analyze
the role of age in the occurrence of NEs. The relationship between
montelukast and NEs in children and adults was analyzed using the
medical concept of adult age. The results showed RR of 0.87 and 95%CI
of 0.71 to 1.06 (P=0.16). We cannot rule out the effect of age on the
overall outcome. Most of the data collected by the pharmacovigilance
institute were from children, whereas the majority of the patients in
our study were adults.4-6,8,11-14The study population
is different from previous studies and may have a remarkable impact on
the results.
Simultaneously, we analyzed the occurrence of adverse events in
combination with montelukast and some commonly used drugs for rhinitis
or asthma, such as loratadine/budesonide. Loratadine is an H1 receptor
antagonist that is used in rhinitis and asthma. Our analysis showed that
loratadine can significantly improve the symptoms of rhinitis and asthma
when used in combination with montelukast.35Budesonide is a hormone drug that combined with
montelukast, and double dose of glucocorticoids showed similar
improvement in patients.28To clarify the relationship
between montelukast and the occurrence of adverse mental events, we
analyzed allergic rhinitis and asthma, respectively. Taking loratadine
or inhalation of budesonide and montelukast in combination or alone, the
occurrence of NEs was not statistically significant
(P>0.05) in the montelukast group compared with the control
group. Considering the effect of medication and the side effects of
hormone drugs, combination medication may be more effective.
Based on our results, no significant association was found between
montelukast and NE events in patients with rhinitis or asthma. We
hypothesized whether the NE is related to the disease. Timonen et
al36 and Kovacs37et al. found that
people with allergies likely develop depression than healthy people.
This finding may be due to the disorders of the hypothalamic
pituitary-adrenal axis and sympathetic adrenal medulla systems and the
changes in the secretion of cytokines in the body, which caused patients
to be affected by emotional and behavioral factors in daily life,
depression, and other neuropsychiatric adverse events. Asthma is a
chronic disease, and the repeated attacks of the disease bring severe
mental suffering to the patients. The inflammatory state in the body
during the onset of asthma leads to an increase in pro-inflammatory
cytokines, which are associated with the development of depression.38In addition, animal studies have found that after
increasing the cholinergic response in rats, rats likely develop
tracheal constriction and airway inflammation, thereby increasing the
occurrence of NEs.39,40The abovementioned research
indicates that NE may be caused by airway allergic disease. However, we
were unable to carry out further research because of insufficient data.
All but one of the
studies32included in this paper were of good quality.
The major funnel plots were symmetrical in appearance without evident
publication bias Begg and Egger. Our meta-analysis showed no significant
increase in the incidence of NEs in patients with allergic rhinitis and
asthma compared with placebo (P>0.05).
This study has certain limitations. First, the effect of the disease on
the results cannot be excluded. Second, considering that the study was
not designed to report adverse drug reactions, no detailed record of
their occurrence was found. Finally, the data of some pharmacovigilance
research databases6,7,11-15,17annot be combined and
analyzed, which further reduce the reliability of the results of the
article and affect the quality of the literature.