Efficacy of Montelukast–Antihistamine Combination Therapy Versus Antihistamine Monotherapy in Allergic Rhinitis: A Systematic Review and Meta-Analysis

Ji-Sun Kim; Gulnaz Stybayeva; Se Hwan Hwang

doi:10.21053/ceo.2025-00201

Clinical and Experimental Otorhinolaryngology > Epub ahead of print

Kim, Stybayeva, and Hwang: Efficacy of Montelukast–Antihistamine Combination Therapy Versus Antihistamine Monotherapy in Allergic Rhinitis: A Systematic Review and Meta-Analysis

Original Article

Clinical and Experimental Otorhinolaryngology 2025; ceo.2025-00201.

Published online: September 17, 2025

DOI: https://doi.org/10.21053/ceo.2025-00201

Efficacy of Montelukast–Antihistamine Combination Therapy Versus Antihistamine Monotherapy in Allergic Rhinitis: A Systematic Review and Meta-Analysis

Ji-Sun Kim¹

, Gulnaz Stybayeva²

, Se Hwan Hwang³

¹Department of Otolaryngology-Head and Neck Surgery, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

²Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA

³Department of Otolaryngology-Head and Neck Surgery, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea

Corresponding author: Se Hwan Hwang Department of Otolaryngology-Head and Neck Surgery, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 327 Sosa-ro, Wonmi-gu, Bucheon 14647, Korea
Tel: +82-32-340-7044, Fax: +82-32-340-2674 Email: yellobird@catholic.ac.kr

Received July 8, 2025 Revised September 13, 2025 Accepted September 17, 2025

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objectives.

Allergic rhinitis (AR) can substantially compromise daily functioning and well-being, and many patients require more than a single agent to obtain satisfactory symptom control. This study examined whether adding montelukast to antihistamine could manage AR symptoms and quality-of-life outcomes effectively.

Methods.

A review was performed in PubMed, Embase, Medline, Scopus, the Cochrane Library, and Google Scholar to identify eligible studies reported through April 2025. Eligible studies compared combination therapy with montelukast plus antihistamine against antihistamine monotherapy and reported nasal symptoms or rhinoconjunctivitis quality of life questionnaire (RQLQ) scores. Treatment effects were further examined by antihistamine class.

Results.

Fifteen studies including 2,882 subjects were analyzed. Combination therapy significantly improved daytime nasal symptoms (standardized mean difference [SMD] [95% CI], 0.44 [0.21–0.67]), nighttime nasal symptoms (0.12 [0.01–0.23]), and RQLQ scores (0.14 [0.00–0.27]) versus monotherapy. Individual nasal or ocular symptoms, sneezing, nasal obstruction, and rhinorrhea improved significantly, while nasal itching and ocular symptoms did not. Combinations with desloratadine and levocetirizine showed greater benefits than those with loratadine or fexofenadine.

Conclusion.

Montelukast–antihistamine combination therapy reduced overall symptoms and improved quality of life versus antihistamine monotherapy. The magnitude of benefit appears to vary depending on the specific antihistamine used, highlighting the possible value of individualized treatment strategies in the treatments of AR.

Keywords: Montelukast; Allergic Rhinitis; Histamine Antagonists; Drug Combinations; Meta-Analysis

INTRODUCTION

Allergic rhinitis (AR) represents an immunoglobulin E (IgE)-driven inflammatory condition, in which exposure to inhaled allergens triggers nasal blockage, rhinorrhea, sneezing, and pruritus, often accompanied by ocular manifestations [1]. It affects approximately 10%–40% of the global population, with a steadily increasing prevalence in industrialized countries over recent decades [2]. AR represents a substantial public health burden, frequently leading to sleep disturbances, difficulty focusing, diminished performance at work or school, and constraints on social engagement [3]. Symptom severity correlates directly with reductions in daily well-being and productivity [4,5].

In AR, the condition develops through a complex interplay between inflammatory mediators and neural pathways. Upon allergen exposure, mast cells bearing IgE on their surface are triggered to degranulate, releasing preformed mediators including histamine. This activation also engages downstream pathways that produce additional inflammatory molecules, including prostaglandins, leukotrienes, and multiple cytokines [6,7]. Oral H1-antihistamines counteract histamine-mediated symptoms by preventing histamine from engaging H1 receptors, thereby reducing sneezing, nasal discharge, and pruritus [8]. Leukotriene receptor antagonists (LTRAs), such as montelukast, reduce nasal congestion, mucosal edema, and chronic inflammation by blocking cysteinyl leukotriene pathways [9,10].

Although oral antihistamines are effective, monotherapy often fails to control the full spectrum of AR symptoms. Combining antihistamines with montelukast offers a mechanistic rationale for enhanced symptom control by targeting complementary inflammatory pathways, potentially benefiting patients with predominant nasal congestion or inadequate response to monotherapy [11]. However, the current literature contains notable gaps. Few studies have compared the effectiveness of different antihistamine-montelukast combinations, and available evidence regarding symptom-specific and quality of life outcomes remains inconsistent. Moreover, variability in study design and outcome assessment further complicates the interpretation of therapeutic benefits across diverse AR symptom profiles [12,13].

This study systematically compared montelukast–antihistamine regimens with antihistamine monotherapy and determined whether the treatment effect varies by antihistamine type. To address this, we performed prespecified subgroup analyses for desloratadine, levocetirizine, loratadine, and fexofenadine when combined with montelukast. Symptom-specific outcomes were also evaluated for rhinorrhea, sneezing, nasal obstruction, nasal itching, ocular manifestations, and for both day and night nasal symptom scores. Through systematic analysis using standardized effect sizes, we sought to elucidate the sources of inconsistency in the reported performance of different combination regimens.

MATERIALS AND METHODS

Search strategy

Comprehensive research was conducted through PubMed, Medline, Embase, Scopus, Google Scholar, and the Cochrane Library for studies published through April 2025. Eligible studies evaluated drug treatments comparing combination therapy with antihistamines and montelukast versus antihistamine monotherapy, assessing symptom and quality of life scores in individuals with AR. Two reviewers (JSK and SHH) evaluated titles and abstracts, removed duplicate records, and identified studies eligible for full-text assessment. The selection workflow for systematic reviews is presented in Fig. 1.

Data extraction and risk of bias assessment

A structured template was used to extract the data [14,15]. For each study, details on participant characteristics (sample size, age distribution, sex, and country), treatment assignments, and reported outcomes were collected. Symptom changes from baseline to post-treatment were evaluated, including scores for specific nasal symptoms (sneezing, itching, nasal obstruction, and rhinorrhea), ocular symptoms, daytime and nighttime nasal symptom composites, and the rhinoconjunctivitis quality of life questionnaire (RQLQ). In most studies, nasal and ocular symptom severity was rated on a four-level ordinal scale (0=none to 3=severe), although some studies employed alternative scoring systems such as a visual analog scale (0–5 or 0–10). Daytime nasal symptom scores were most often calculated by combining four components (sneezing, nasal itching, rhinorrhea, and nasal obstruction) into a single composite measure. Nighttime scores were derived from either three items (such as mouth breathing, postnasal drip, and sleep disturbance) or four items, depending on the study. Eye symptoms were most often assessed using a 3-item composite scale (0–3 each). The RQLQ was consistently measured using a 7-point Likert scale (spanning 0, indicating absence of functional deficit, to 6, indicating the most pronounced deficit) (Supplementary Table 1). Treatment groups consisted of montelukast–antihistamine combination therapy (loratadine, levocetirizine, fexofenadine, or desloratadine) and control groups receiving antihistamines alone. The relative effectiveness of combination therapy versus monotherapy was assessed. Assessment of bias in the randomized controlled trials was demonstrated in Supplementary Table 2 [16].

Statistical methods

Statistical analyses were undertaken using R program (version 4.3.1; R Foundation for Statistical Computing), which was used to pool effect estimates and compare outcomes among the included studies. Continuous outcomes were assessed through comparisons of group means and standard deviations. In this study, effect sizes were measured with standardized mean differences (SMDs) to summate and measure the outcomes on different scales. Variability across studies was examined with Cochran’s Q statistic and further described using the I² value. Publication bias was investigated by reviewing Egger’s regression test and funnel plot symmetry. In addition, subgroup and sensitivity analyses were performed to explore potential or influence factors.

To enhance clinical interpretability, we additionally calculated raw mean differences (MDs) for the RQLQ (7-point scale) in studies using this consistent scoring system and compared the results with established minimal clinically important difference (MCID) thresholds [17]. Raw MDs were not used for daytime or nighttime nasal symptom scores, nor for individual nasal or ocular symptoms, because the included studies employed heterogeneous scoring systems that varied in scale structure, number of items, and scoring ranges.

RESULTS

A total of 2,882 participants from 15 eligible studies were included in the final analysis [12,13,18-30]. An overview of these studies is provided in Table 1. The methodological quality of the randomized controlled trials was assessed using the Cochrane Risk of Bias tool, with detailed evaluations presented in Supplementary Table 2. For non-randomized controlled trials, quality was assessed based on predefined criteria, as summarized in Supplementary Table 3. The protocol was registered in advance on the Open Science Framework (https://osf.io/4sedu/).

Direct comparison of symptom and quality of life effects: combination therapy vs antihistamine monotherapy

Combination therapy significantly improved overall symptoms and quality of life compared to antihistamine monotherapy. Significant effects were observed in daytime nasal symptoms (SMD [95% CI], 0.44 [0.21–0.67]; I²=76.8%), nighttime nasal symptoms (SMD [95% CI], 0.12 [0.01–0.23]; I²=0.0%), and quality of life (SMD [95% CI], 0.14 [0.00–0.27]; I²=24.6%) (Fig. 2). Notably, while the improvement in nighttime nasal symptoms was statistically significant, the effect size was small. Considerable inter-study heterogeneity (I² >50%) was noted in some outcomes, potentially attributable to variations in the type of antihistamine used in the combination group, which were not distinguished in the overall analysis.

In the subgroup analysis by antihistamine type, montelukast combined with desloratadine showed the most notable effect sizes, with statistically significant improvements in daytime symptoms (SMD [95% CI], 1.06 [0.56–1.56]; I²=0%) and RQLQ (SMD [95% CI], 0.58 [0.13–1.03]; I²=7.1%), although nighttime symptoms did not show a statistically significant improvement (SMD [95% CI], 0.15 [–0.29 to 0.59]; I²=0%) (Table 2). The levocetirizine combination showed statistically significant benefits for both daytime symptoms (SMD [95% CI], 0.59 [0.18–1.01]; I²=63.2%) and nighttime symptoms (SMD [95% CI], 0.25 [0.04–0.46]; I²=29.7%), whereas RQLQ improvements were not statistically significant (SMD [95% CI], 0.11 [–0.16 to 0.39]; I²=0%). In contrast, combination therapy with loratadine did not result in statistically significant improvements in daytime symptoms (SMD [95% CI], 0.30 [–0.04 to 0.64]; I²=82.7%), nighttime symptoms (SMD [95% CI], 0.05 [–0.09 to 0.19]; I²=0%), or RQLQ (SMD [95% CI], 0.09 [–0.07 to 0.25]; I²=NA). Similarly, the fexofenadine–montelukast combination therapy did not lead to statistically significant improvements in daytime symptoms (SMD [95% CI], 0.23 [–0.16 to 0.61]; I²=0%) or nighttime symptoms (SMD [95% CI], 0.31 [–0.29 to 0.90]; I²=NA). Additionally, an exploratory analysis of raw MDs for RQLQ revealed an overall pooled MD of approximately 0.17, and even the desloratadine–montelukast combination achieved only about 0.33, both remaining below the commonly accepted MCID threshold of 0.5 [17].

Direct comparison of individual nasal symptom effects: combination therapy vs. antihistamine monotherapy

Combination therapy with montelukast and antihistamines significantly improved several individual nasal symptoms compared to antihistamine monotherapy. Pooled analysis showed significant improvements in sneezing (SMD [95% CI], 0.42 [0.10–0.74]; I²=68.3%), nasal obstruction (SMD [95% CI], 0.55 [0.26–0.84]; I²=73.4%), and rhinorrhea (SMD [95% CI], 0.19 [0.06–0.32]; I²=42.0%) (Fig. 3). However, improvements in nasal itching (SMD [95% CI], 0.08 [–0.05 to 0.22]; I²=22.8%) and eye symptoms (SMD [95% CI], 0.55 [–0.20 to 1.30]; I²=95.8%) were not statistically significant.

In the subgroup analysis, the desloratadine–montelukast combination demonstrated the greatest improvements across individual symptoms compared to antihistamine monotherapy (Table 3). Significant improvements were identified in sneezing (SMD [95% CI], 1.07 [0.57–1.57]; I²=0%), nasal obstruction (SMD [95% CI], 0.92 [0.49–1.36]; I²=20.4%), and rhinorrhea (SMD [95% CI], 0.55 [0.08–1.03]; I²=33.3%), while improvement in nasal itching was not significant (SMD [95% CI], 0.03 [–0.44 to 0.50]; I²=67.0%).

The levocetirizine–montelukast combination therapy resulted in significant improvements in sneezing (SMD [95% CI], 0.68 [0.24–1.11]; I²=0%), nasal obstruction (SMD [95% CI], 0.87 [0.50–1.23]; I²=0%), and rhinorrhea (SMD [95% CI], 0.66 [0.23–1.10]; I²=0%). Nasal itching showed a significant improvement, though the effect size was smaller (SMD [95% CI], 0.49 [0.06–0.92]; I²=0%).

In contrast, combination therapies involving montelukast and loratadine or montelukast and fexofenadine did not show significant improvements in any individual nasal symptoms compared to antihistamine monotherapy. Additionally, improvements in eye symptoms were not statistically significant in any subgroup analysis, indicating that montelukast-based combination therapy did not provide additional benefits over antihistamine monotherapy for ocular symptoms.

Sensitivity analyses

The sensitivity analyses showed that the pooled estimates for individual nasal symptoms and daytime nasal symptom scores were consistent with the main analyses, supporting the robustness of these outcomes. In contrast, the findings for eye symptoms, nighttime symptom scores, and RQLQ scores varied depending on the study excluded, suggesting that these conclusions may not be robust and could be influenced by a small subset of studies. The detailed results are presented in Supplementary Figs. 1 and 2. These findings indicate that the results for daytime and individual nasal symptoms are stable. In contrast, additional research is required to reinforce the evidence base for eye symptoms, nighttime symptoms, and RQLQ, and these outcomes should be interpreted cautiously in clinical contexts.

DISCUSSION

This meta-analysis systematically evaluates whether the effectiveness of montelukast-based combination therapy varies by antihistamine type. Overall, the combination therapy showed significantly superior improvements in daytime and nighttime nasal symptom measures and resulted in better RQLQ outcomes compared with antihistamine monotherapy. Subgroup analyses revealed that desloratadine– and levocetirizine–montelukast combinations produced greater benefits across multiple symptom domains, whereas loratadine– and fexofenadine–montelukast combinations showed no significant advantages. Improvements in nasal itching and eye symptoms were not observed in any subgroup, suggesting limited effectiveness for these manifestations. Although raw MDs for RQLQ remained below the MCID threshold, indicating modest clinical impact at the individual level, the differential benefits observed among antihistamines support the potential value of individualized treatment strategies in patients with persistent symptoms.

AR is primarily mediated by IgE-driven allergic inflammation, resulting in nasal and ocular symptoms such as sneezing, rhinorrhea, nasal congestion, nasal itching, and eye irritation. Pharmacologic management of AR typically involves the use of intranasal corticosteroids (INCS), oral H1-antihistamines, and LTRAs [31]. H1-antihistamines act by blocking the interaction between histamine and H1 receptors expressed on epithelial cells, endothelial cells, and sensory neurons [32]. By blocking receptor activation, these agents reduce histamine-induced vasodilation, increased vascular permeability, stimulation of sensory nerves, and subsequent inflammatory cascades. Through these mechanisms, H1-antihistamines primarily mitigate histamine-mediated symptoms, particularly sneezing, rhinorrhea, and nasal itching [33]. Meanwhile, LTRAs, such as montelukast, block the biological actions of cysteinyl leukotrienes, which contribute to airway inflammation, enhanced vascular permeability, and mucus hypersecretion [34]. In patients with AR, montelukast not only improves nasal symptoms but also provides additional clinical benefits for individuals with concomitant asthma [35].

Second-generation antihistamines are favored clinically because they offer better safety characteristics and cause markedly less sedation than first-generation agents [32]. Although all second-generation H1-antihistamines share the primary mechanism of histamine receptor blockade, notable pharmacologic differences exist among agents [36]. Variations in receptor binding affinity, onset and duration of action, lipophilicity, and additional anti-inflammatory properties may contribute to differences in clinical efficacy [37,38]. Our study revealed that despite belonging to the same pharmacologic class, combinations of montelukast with different second-generation H1-antihistamines demonstrated varying degrees of clinical outcomes. Combinations with desloratadine and levocetirizine showed greater improvements across various symptom domains and individual symptoms compared to antihistamine monotherapy. However, combinations involving loratadine or fexofenadine did not consistently demonstrate additional benefits over monotherapy. These findings suggest that the effectiveness of combination therapy may differ depending on the specific antihistamine agent used. Although further clinical and experimental studies are needed to clarify these observations, previous studies have indicated that desloratadine and levocetirizine may possess anti-inflammatory properties that extend beyond their roles as H₁-receptor blockers [39,40]. These properties may potentially contribute to enhanced therapeutic effects when combined with montelukast.

The current understanding of AR pathophysiology extends beyond the classical histamine and leukotriene pathways, encompassing a complex network of inflammatory mediators, including neurogenic peptides, that collectively drive the inflammatory response [2]. In our study, while combination therapy significantly improved several nasal symptoms, it did not consistently improve nasal itching or ocular symptoms. These findings suggest that ocular symptoms in AR may be driven by mechanisms extending beyond histamine and leukotriene pathways, including ocular surface inflammation, tear film instability, and sensory nerve hypersensitivity. In chronic cases, these processes can lead to structural remodeling of the ocular surface [41,42]. Consequently, combination therapy with montelukast and antihistamines alone may be insufficient for comprehensive symptom control in patients with significant ocular involvement. Topical therapies, including antihistamines, dual-acting agents, and mast cell stabilizers, are important therapeutic options for managing ocular symptoms [43,44]. In addition, INCS exert broad anti-inflammatory effects by targeting multiple inflammatory pathways and remain the cornerstone of AR management, recommended for patients who continue to experience symptoms despite combination therapy [45].

This meta-analysis presents a systematic assessment of the effectiveness of montelukast-based combination therapy across different second-generation antihistamines in AR. By systematically comparing symptom-specific outcomes, our findings offer valuable insights into the variability of treatment responses and highlight the potential need for individualized combination strategies. However, several limitations of this analysis warrant consideration. First, the number of studies contributing to each antihistamine subgroup was limited, which constrains the generalizability of the results. Second, the heterogeneity observed in some outcomes, particularly for daytime and nighttime nasal symptoms, suggests variability in study designs, patient populations, and treatment durations. Third, the analyses primarily compared combination therapy to antihistamine monotherapy, without direct head-to-head comparisons between different antihistamine agents. Therefore, any inference about the relative superiority of specific combinations should be viewed cautiously. Fourth, most studies did not stratify results by disease severity, the presence of comorbid asthma, or baseline symptom profiles. In addition, five trials did not clearly report their policy on INCS use, which could also influence treatment outcomes. Finally, although we performed MD analyses to enhance clinical interpretability, most observed differences did not exceed MCID thresholds. This underscores the importance of distinguishing statistical significance from clinical relevance in interpreting combination therapy outcomes.

While most raw MDs did not exceed established MCID thresholds, SMDs demonstrated statistically significant and consistent benefits of combination therapy across multiple symptom domains. This discrepancy reflects the different interpretive frameworks of these metrics. MCID captures perceptible change at the individual level within single trials, whereas SMD reflects aggregated effects across multiple studies and accommodates heterogeneous outcome scales, thereby complementing the perspective provided by MD analyses [46]. Although individual improvements may appear modest, the cumulative benefit observed in meta-analysis may still translate into meaningful symptom relief for patients with persistent or severe disease. In particular, combinations with desloratadine or levocetirizine showed greater benefits across several domains, highlighting the importance of individualized treatment strategies and supporting montelukast-based combination therapy as a valuable option when antihistamine monotherapy fails to achieve optimal symptom control.

HIGHLIGHTS

▪ Compared with antihistamine monotherapy, combination therapy significantly improved both daytime and nighttime symptoms, along with quality-of-life outcomes.

▪ Significant improvements in nasal obstruction, sneezing, and rhinorrhea were observed with combination therapy, whereas nasal itching and ocular symptoms showed no benefit over monotherapy.

▪ Montelukast combined with desloratadine or levocetirizine showed greater benefits than with loratadine or fexofenadine.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (2022R1F1A1066232).

AUTHOR CONTRIBUTIONS

Conceptualization: JSK, GS, SHH. Methodology: JSK, SHH. Software: SHH. Validation: SHH. Formal analysis: JSK, SHH. Investigation: JSK, SHH. Data curation: JSK, SHH. Writing–original draft preparation: JSK, SHH. Writing–review and editing: JSK, SHH. Visualization: JSK, SHH. Supervision: JSK, GS, SHH. All authors read and agreed to the published version of the manuscript.

SUPPLEMENTARY MATERIALS

Supplementary materials can be found online at https://doi.org/10.21053/ceo.2025-00201.

Supplementary Table 1.

Symptom assessment scales across included studies

ceo-2025-00201-Supplementary-Table-1.pdf

Supplementary Table 2.

Individual randomized controlled trial methodological quality

ceo-2025-00201-Supplementary-Table-2.pdf

Supplementary Table 3.

Quality of individual non-randomized controlled trial methodology

ceo-2025-00201-Supplementary-Table-3.pdf

Supplementary Fig. 1.

Sensitivity analysis for daytime nasal symptoms, nighttime nasal symptoms, and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores. Forest plots showing the results of sensitivity analyses for daytime nasal symptoms (A), nighttime nasal symptoms (B), and RQLQ scores (C). Each analysis was repeated by omitting one study at a time to evaluate the robustness of the pooled estimates. SMD, standardized mean difference; I², heterogeneity index; MD, mean difference.

ceo-2025-00201-Supplementary-Fig-1.pdf

Supplementary Fig. 2.

Sensitivity analysis for individual nasal and eye symptom scores. Sneezing (A), nasal itching (B), nasal obstruction (C), rhinorrhea (D), and eye symptom (E) are shown. Each analysis was repeated by omitting one study at a time to assess the influence of individual studies. SMD, standardized mean difference; I², heterogeneity index.

ceo-2025-00201-Supplementary-Fig-2.pdf

Fig. 1.

Study selection diagram.

Fig. 2.

Direct comparison of changes in total symptom scores and quality of life between montelukast-based combination therapy and antihistamine monotherapy. Daytime total symptom score (A), nighttime total symptom score (B), and Rhinoconjunctivitis Quality of Life Questionnaire (C) are shown. SD, standard deviation; SMD, standardized mean difference; I², heterogeneity index; Lora, loratadine; Mon, montelukast; DesL, desloratadine; LevoC, levocetirizine; Fexof, fexofenadine.

Fig. 3.

Direct comparison of changes in individual symptoms between montelukast-based combination therapy and antihistamine monotherapy. Sneezing (A), nasal itching (B), nasal obstruction (C), rhinorrhea (D), and eye symptom (E) are shown. SD, standard deviation; SMD, standardized mean difference; I², heterogeneity index; Lora, loratadine; Mon, montelukast; DesL, desloratadine; LevoC, levocetirizine; Fexof, fexofenadine.

Table 1.

Summary of the studies included in the meta-analysis

Study	Nation	Method	Total number	Age (yr)	Rhinitis type	Treatment	Duration (wk)	Outcome
Meltzer et al. (2000) [18]	USA	Multicenter RCT	460	15–75	SAR	Montelukast (10/20 mg), loratadine 10 mg, combination (montelukast+loratadine), or placebo	2	Daytime nasal symptoms, daytime eye symptoms, nighttime nasal symptoms
Wilson et al. (2002) [19]	UK	Double-blind, placebo-controlled crossover RCT	37	Mean, 37.0 (SE, 2.0)	SAR	Fexofenadine 120 mg, combination (montelukast 10 mg+loratadine 10 mg), or placebo	2	Daytime nasal symptoms, individual nasal symptoms, daytime eye symptoms
Nayak et al. (2002) [20]	USA	Multicenter, double-blind, placebo-controlled parallel-group RCT	758	15–82	SAR	Montelukast (10/20 mg), loratadine 10 mg, combination (montelukast+loratadine), or placebo	2	Daytime nasal symptoms, individual nasal symptoms, daytime eye symptoms, nighttime nasal symptoms, rhinoconjunctivitis quality-of-life
Ciebiada et al. (2006) [21]	Poland	Double-blind, placebo-controlled crossover RCT	40	18–65	PAR	Montelukast 10 mg, desloratadine 5 mg, combination, or placebo	6	Daytime nasal symptoms, individual nasal symptoms, daytime eye symptoms
Ciebiada et al. (2008) [22]	Poland	Double-blind, placebo-controlled crossover RCT	40	18–65	PAR	Montelukast 10 mg, desloratadine 5 mg, combination, or placebo	6	Nighttime nasal symptoms, rhinoconjunctivitis quality-of-life
Li et al. (2009) [12]	Hong Kong	Placebo-controlled RCT	44	6–18	PAR	Fexofenadine 60 mg for <12 yr and 120 mg for ≥12 yr, combination (fexofenadine+montelukast (5 mg for <14 yr or 10 mg for ≥14 yr)	16	Daytime nasal symptoms, individual nasal symptoms, nighttime nasal symptoms
Lu et al. (2009) (study 1) [23]	Belgium	Parallel-group phase 2 RCT	402	15–85	SAR	Beclomethasone 200 µg, placebo, combination (montelukast 10 mg+loratadine 10 mg), montelukast 10 mg, or loratadine 10 mg	2	Daytime nasal symptoms
Lu et al. (2009) (study 2) [23]	Belgium	Parallel-group phase 2 RCT	476	15–85	SAR	Combination (montelukast 10 mg+loratadine 10 mg), montelukast mg, or loratadine mg	2	Daytime nasal symptoms
Gupta et al. (2010) [24]	India	Prospective, open-label, parallel-group RCT	95	18–60	AR	Levocetirizine 5 mg, combination (levocetirizine 5 mg+montelukast 10 mg)	6	Daytime nasal symptoms, daytime eye symptoms, nighttime nasal symptoms
Ciebiada et al. (2011) [13]	Poland	Double-blind, placebo-controlled, crossover, two-arm RCT	40	18–65	PAR	Montelukast 10 mg, desloratadine 5 mg, combination (montelukast 10 mg+desloratadine 5 mg), or placebo	6	Individual nasal symptoms
Son et al. (2013) [25]	Korea	Retrospective chart review	60	Mean, 29.3 (SD, 2.9)	PAR	Fexofenadine 120 mg, combination (fexofenadine 10 mg+montelukast 10 mg)	Mean, 6.7 (SD, 4.6)	Individual nasal symptoms
Erdođan et al. (2014) [26]	Türkiye	Double-blind, cross-sectional RCT	40	17–44	PAR	Desloratadine 5 mg, combination (desloratadine 5 mg+montelukast 10 mg)	6	Nighttime nasal symptoms, rhinoconjunctivitis quality-of-life
Andhale et al. (2016) [27]	India	Prospective RCT	75	15–75	PAR	Levocetirizine 5 mg, combination (levocetirizine 5 mg+montelukast 10 mg)	2	Individual nasal symptoms
Zhou et al. (2020) [28]	China	Prospective RCT	104	18–80	AR	Montelukast 10 mg, combination (montelukast+loratadine), or placebo	4	Daytime nasal symptoms
Panchal et al. (2020) [29]	India	Double-blind, multicenter, phase III RCT	166	18–60	SAR	Montelukast 10 mg, combination (montelukast 10 mg+levocetirizine 5 mg), or levocetirizine 5mg alone	2	Daytime nasal symptoms, daytime eye symptoms, nighttime nasal symptoms, rhinoconjunctivitis quality-of-life
Ghanbari et al. (2024) [30]	Iran	Open-label RCT	45	6–14	PAR	Desloratadine syrup (2.5–5 mg), montelukast 5 mg, combination (desloratadine+montelukast)	8	Daytime nasal symptoms, individual nasal symptoms

RCT, randomized controlled trial; SAR, seasonal allergic rhinitis; SE, standard error; PAR, perennial allergic rhinitis; SD, standard deviation.

Table 2.

Subgroup analysis of total symptom scores and quality of life following montelukast-based combination therapy versus antihistamine monotherapy

	Daytime	Nighttime	RQLQ
SMD	0.44 (0.21 to 0.67)	0.12 (0.01 to 0.23)	0.14 (0.00 to 0.27)
SMD	I²=76.8%	I²=0%	I²=24.6%
Loratadine+montelukast	(n=6)	(n=2)	(n=1)
	0.30 (–0.04 to 0.65)	0.05 (–0.09 to 0.19)	0.09 (–0.07 to 0.25)
	I²=82.7%	I²=0%	NA
Desloratadine+montelukast	(n=2)	(n=2)	(n=2)
	1.06 (0.56 to 1.56)	0.15 (–0.29 to 0.59)	0.58 (0.13 to 1.03)
	I²=0%	I²=0%	I²=7.1%
Levocetirizine+montelukast	(n=3)	(n=4)	(n=2)
	0.59 (0.18 to 1.01)	0.20 (0.04 to 0.46)	0.12 (–0.16 to 0.39)
	I²=63.2%	I²=29.7%	I²=0.0%
Fexofenadine+montelukast	(n=2)	(n=1)	–
	0.23 (–0.16 to 0.62)	0.31 (–0.29 to 0.90)
	I²=0.0%	I²=NA
P-value	0.043	0.417	0.125

Values are presented as SMD (95% CI).

RQLQ, Rhinoconjunctivitis Quality of Life Questionnaire; SMD, standardized mean difference; I², heterogeneity index; n, number of groups included in the analysis; NA, not available.

Table 3.

Subgroup analysis of individual nasal symptom improvements following montelukast-based combination therapy versus antihistamine monotherapy

	Sneezing	Itching	Obstruction	Rhinorrhea	Eye symptom
SMD	0.42 (0.10 to 0.74)	0.08 (–0.05 to 0.22)	0.55 (0.26 to 0.84)	0.19 (0.06 to 0.32)	0.55 (–0.20 to 1.30)
SMD	I²=68.3%	I²=22.8%	I²=73.4%	I²=42.0%	I²=95.8%
Loratadine+montelukast	(n=2)	(n=2)	(n=2)	(n=2)	(n=3)
	0.07 (–0.06 to 0.24)	0.06 (–0.09 to 0.21)	0.08 (–0.11 to 0.26)	0.10 (–0.05 to 0.25)	0.09 (–0.05 to 0.22)
	I²=0%	I²=0%	I²=11.5%	I²=0%	I²=0%
Desloratadine+montelukast	(n=2)	(n=2)	(n=3)	(n=2)	(n=1)
	1.07 (0.58 to 1.57)	0.03 (–0.44 to 0.50)	0.93 (0.49 to 1.36)	0.55 (0.08 to 1.03)	0.53 (–0.11 to 1.16)
	I²=0%	I²=67.0%	I²=20.4%	I²=33.3%	NA
Levocetirizine+montelukast	(n=2)	(n=2)	(n=3)	(n=2)	(n=3)
	0.68 (0.24 to 1.11)	0.49 (0.06 to 0.92)	0.87 (0.50 to 1.23)	0.66 (0.23 to 1.10)	0.96 (–0.86 to 2.78)
	I²=0%	I²=0%	I²=0%	I²=0%	I²=98.0%
Fexofenadine+montelukast	(n=2)	(n=1)	(n=2)	(n=1)	–
	0.01 (–0.43 to 0.45)	–0.22 (–0.82 to 0.37)	0.19 (–0.19 to 0.58)	0.10 (–0.41 to 0.61)
	I²=21.6%	NA	I²=0%	NA
P-value	0.0002	0.202	<0.001	0.041	0.270

Values are presented as SMD (95% CI).

SMD, standardized mean difference; I², heterogeneity index; n, number of groups included in the analysis; NA, not available.

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