Question | |
Should oral H1-antihistamines vs. leukotriene receptor antagonists be used for the treatment of allergic rhinitis? | |
Population: | Patients with allergic rhinitis |
Intervention: | oral H1-antihistamines |
Comparison: | leukotriene receptor antagonists |
Main outcomes: | Nasal symptoms Ocular symptoms Quality of life Adverse events (any) Serious adverse events |
Setting: | |
Perspective: | Clinical recommendation – patient perspective |
Background: | Oral antihistamines and leukotriene receptor antagonists may both be used for the treatment of allergic rhinitis. While oral antihistamines are widely used as first-line treatment, leukotriene receptor antagonists are often used in patients with coexisting asthma or when oral antihistamines are not well tolerated |
Conflict of interests: | AWMF conflict of interest declaration and management policies were applied, the assessment performed by the AWMF with guidance and help from Juan Jose Yepes Nuñez. |
Assessment
ProblemIs the problem a priority? | ||
Judgement | Research evidence | Additional considerations |
Allergic rhinitis (AR) is a common condition affecting 18.1% of the population, and its symptoms can significantly reduce the quality of life and pose a high economic burden (mainly because of indirect costs related to lost school days and workdays). [Savoure] Studies of patients consulting general practitioners for AR reported that 18–48 % had symptoms that were not controlled by pharmacotherapy. [Bousquet, Bhattacharyya, Vandenplas] Despite the bothersome nature of symptoms, AR is often trivialized by the patient – only 45% seek medical advice or treatment for their condition, which results in under-treatment and poor control of symptoms. [Linneberg] Problems related to disease Economic burden A systematic review performed to estimate the financial burden of AR in European countries [Linneberg] suggests that the GP services bore the majority of the direct costs for AR. However, the majority of the overall cost burden correspond to indirect costs caused by high absenteeism and presenteeism. In the United States, annual costs for medications for rhinitis patients can be estimated at approximately $1.3 billion. In total, direct costs are estimated to be >$4.6 billion for rhinitis management, including treatment, allergy testing, clinical visits and hospital procedures. [Roland] Similar findings were found for Asia. An analysis of the indirect costs associated with insufficiently treated AR and urticaria patients revealed an annual burden of USD 105.4 billion. This translates to a cost ranging from USD 1,137 to USD 2,195 per patient due to absenteeism and presenteeism [ Kulthanan] Clinical burden The median prevalence of allergic rhinitis was found to be 18.1%, based on a dataset that included 310 reported prevalences. The prevalence of AR ranged from as low as 1.0% to as high as 54.5%.
These statistics indicate that AR is a relatively common condition affecting a significant portion of the population, with variations in prevalence observed across different regions or studies. [Savouré] References:
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Desirable EffectsHow substantial are the desirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
Nasal symptoms In a systematic review with network meta-analysis performed by our team [1] and considering references obtained in a previous systematic review [2], the improvement of nasal symptoms was assessed in patients under oral H1-antihistamines (OAH) and compared with that registered in patients receiving leukotriene receptor antagonists (LTRA). For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the total nasal symptom score (TNSS; combination of four nasal symptoms and scale of 0-12) results of 38 randomised controlled trials (RCTs). The improvement in the TNSS observed in patients under OAH was higher than that observed for LTRA (mean difference=-0.28; 95%CI=-0.51;-0.04). 98.8% probability of a trivial difference. For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the TNSS results of 12 RCTs. The improvement in the TNSS observed in patients under OAH was higher than that observed for LTRA (mean difference=-0.27; 95%CI=-0.51;-0.03). 76.0% probability of a trivial difference. Ocular symptoms In a systematic review with network meta-analysis performed by our team [1] and considering references obtained in a previous systematic review [2], the improvement of ocular symptoms was assessed in patients under OAH and compared with that registered in patients receiving LTRA. For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the total ocular symptom score (TOSS) results of 10 RCTs, but considering four ocular symptoms and a scale of 0-12. The improvement in the TOSS observed in patients under OAH was higher than that observed for LTRA (mean difference=-0.23; 95%CI=-0.43;-0.02). 98.8% probability of a trivial difference. For patients with perennial allergic rhinitis, no primary studies were identified allowing for the comparison between OAH versus LTRA on their effect on the TOSS. Quality-of-life In a systematic review with network meta-analysis performed by our team [1] and considering references obtained in a previous systematic review [2], the improvement of quality-of-life was assessed in patients under OAH and compared with that registered in patients receiving LTRA. For patients with seasonal allergic rhinitis, it was possible to meta-analytically pool the rhinocojunctivitis quality of life questionnaire (RQLQ; scale of 0-6) results of 23 RCTs. The improvement in the RQLQ was not significantly different when OAH was compared to LTRA (mean difference=-0.04; 95%CI=-0.11;0.04). 99.8% probability of a trivial difference. For patients with perennial allergic rhinitis, it was possible to meta-analytically pool the RQLQ results of 8 RCTs. The improvement in the RQLQ was not significantly different when OAH was compared to LTRA (mean difference=0.03; 95%CI=–0.38;0.43). 6.6% probability of a meaningful improvement. Subgroup considerations: Children and adolescents No studies were identified comparing LTRA versus placebo on nasal symptoms (as assessed by the TNSS), ocular symptoms (as assessed by the TOSS) or the RQLQ. References: 1. Vieira RJ, Gil-Mata S, Ferreira A, Riera-Serra P, Bognanni A, Duarte VH, et al. Efficacy and safety of oral antihistamines for allergic rhinitis: Network meta-analysis. 2025 [Link for the list of studies and certainty of evidence assessments] 2. Krishnamoorthy M et al. Efficacy of Montelukast in Allergic Rhinitis Treatment: A Systematic Review and Meta-Analysis. Drugs. 2020;80(17):1831-1851. | ||
Undesirable EffectsHow substantial are the undesirable anticipated effects? | ||
Judgement | Research evidence | Additional considerations |
Adverse events In a systematic review with network meta-analysis performed by our team [1] and considering references obtained in a previous systematic review [2], the frequency of patients developing at least one adverse event was assessed in patients under oral H1-antihistamines (OAH) and compared with that registered in patients receiving leukotriene receptor antagonists (LTRA). A total of 38 randomised controlled trials (RCTs) reported data on the number of patients with seasonal allergic rhinitis reporting at least one adverse event. The meta-analytical risk ratio was of 1.06 (95% confidence interval=0.90; 1.24) [OAH was associated to 12 more cases per 1000 patients than LTRA; 95%CI = 19 fewer cases to 46 more cases per 1000 patients. Trivial difference]. No evidence was found for perennial allergic rhinitis. Subgroup considerations: Children and adolescents No RCTs were found presenting data on the frequency of adverse events in children under OAH versus those under LTRA. Serious adverse events In a systematic review with network meta-analysis performed by our team [1] and considering references obtained in a previous systematic review [2], the frequency of patients developing at least one serious adverse event was assessed both in patients under OAH and in patients receiving LTRA. For seasonal allergic rhinitis, one RCT reported the frequency of serious adverse events in patients using OAH and LTRA: no serious adverse events were reported in this study. Considering RCTs in which OAH were compared to placebo or other OAHs, a total of 8 serious adverse events were reported in 6485 patients using OAH. None of the serious adverse events were considered to be related to the use of the treatment. No evidence from RCTs was found for perennial allergic rhinitis. Observational studies have pointed to potential (but rare) neuropsychiatric effects—such as nightmares, insomnia, irritability, mood changes [3-4]. Pharmacovigilance data lists depression, suicide ideation, anxiety, aggressivity and insomnia as the most common serious adverse events associated with the use of LTRA. Because of these adverse events, FDA issued a black box warning for montelukast [5]. Subgroup considerations: Children and adolescents No RCTs were found presenting data on the frequency of serious adverse events in children under OAH versus those under LTRA. In pharmacovigilance data, serious adverse events were more commonly reported for children than for adults. References: 1. Vieira RJ, Gil-Mata S, Ferreira A, Riera-Serra P, Bognanni A, Duarte VH, et al. Efficacy and safety of oral antihistamines for allergic rhinitis: Network meta-analysis. 2025 [Link for the list of studies and certainty of evidence assessments] 2. Krishnamoorthy M et al. Efficacy of Montelukast in Allergic Rhinitis Treatment: A Systematic Review and Meta-Analysis. Drugs. 2020;80(17):1831-1851. 3. Al-Shamrani A, et al. Adverse Drug Reactions (ADRs) of Montelukast in Children. Children. 2022;9(11):1783. 4. Paljarvi T et al. Analysis of neuropsychiatric diagnoses after montelukast initiation. JAMA Network Open. 2022;5(5):e2213643. 5. Food and Drug Administration. Singulair (montelukast) and All Montelukast Generics: Strengthened Boxed Warning – Due to Restricting Use for Allergic Rhinitis. 2020. Available at: https://www.fda.gov/safety/medical-product-safety-information/singulair-montelukast-and-all-montelukast-generics-strengthened-boxed-warning-due-restricting-use | Based on the available evidence, the judgment of undesirable effects was considered small for oral H1-antihistamines (OAH) when compared with leukotriene receptor antagonists (LTRA). No serious adverse events related to OAH were reported in trials, while pharmacovigilance data indicated a higher concern for serious neuropsychiatric events associated with LTRA, leading to a black box warning for montelukast. | |
Certainty of evidenceWhat is the overall certainty of the evidence of effects? | ||
Judgement | Research evidence | Additional considerations |
The certainty of evidence was high for 2 out of 6 analyses, moderate for 2 out of 6 analyses, low for 1 out of 6 analyses, and very low for 1 out of 6 analyses.
References: 1. Vieira RJ, Gil-Mata S, Ferreira A, Riera-Serra P, Bognanni A, Duarte VH, et al. Efficacy and safety of oral antihistamines for allergic rhinitis: Network meta-analysis. 2025 [Link for the list of studies and certainty of evidence assessments] | We considered the CoE to be “moderate”, considering that for most outcomes the CoE is either moderate or high. | |
ValuesIs there important uncertainty about or variability in how much people value the main outcomes? | ||
Judgement | Research evidence | Additional considerations |
Utility values Symptoms Regarding specific symptoms, in two studies, utilities (measured by VAS) were lower for severe nasal congestion and severe rhinorrhea compared to severe sneezing, severe throat itching, and severe itchy eyes (CoE: low). When utilities were elicited with the standard gamble technique, severe itchy eyes were rated by US patients as the least preferred AR symptom (CoE: low).  Studies of rating or ranking of outcomes Adults
 Children/caregivers sample: Seven studies assessing children or their caregivers were included in the relative importance analysis. Most of these studies only assessed symptom-related attributes. Similarly to the adult population, a nasal symptom was frequently ranked as the most or second most important attribute (CoE: low). In particular, nasal congestion was identified as the most important attribute in five studies (CoE: low).  | The available evidence on values is based on the relative importance patients place on allergic rhinitis symptoms, regardless of the intervention or comparison. Nasal symptoms—particularly nasal congestion—were consistently ranked as the most important by both adults and caregivers of children. While this information helps identify which outcomes are most valued, it does not provide direct insight into how patients value oral H1-antihistamines compared with leukotriene receptor antagonists. | |
Balance of effectsDoes the balance between desirable and undesirable effects favor the intervention or the comparison? | ||
Judgement | Research evidence | Additional considerations |
Taking into account both benefits and harms of oral antihistamines (OAH) versus leukotriene antagonists (LTRA), we can consider the following:
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Resources requiredHow large are the resource requirements (costs)?” | ||
Judgement | Research evidence | Additional considerations |
Cost of drugs We conducted a survey, having received responses from specialists from 51 countries (mostly in Europe, America and Asia). OAH and LTRA were available in all 51 countries, but there were three countries for which information on the costs of LTRA were not available. The costs of being treated for one year with OAH ranged from 4.7 US Dollars Power Purchase Parity (PPP) [Hong Kong] to 743.3 USD PPP [Argentina] (assuming full adherence to treatment and the choice of the least expensive OAH). This corresponds to weekly costs ranging from 0.1 USD PPP to 14.3 USD PPP. The yearly costs per country associated with the use of OAH are displayed in the following map:  The costs of being treated for one year with LTRA ranges from 8.9 US Dollars Power Purchase Parity (PPP) [Hungary] to 2256.5 USD PPP [Argentina] (assuming full adherence to treatment and option for montelukast). This corresponds to weekly costs ranging from 0.2 USD PPP to 43.4 USD PPP. The yearly costs per country associated with the use of LTRA are displayed in the following map:  In 46 out of the 48 countries, OAH were associated with lower costs than LTRA:  | ||
Certainty of evidence of required resourcesWhat is the certainty of the evidence of resource requirements (costs)? | ||
Judgement | Research evidence | Additional considerations |
Given that oral antihistamines and leukotriene receptor antagonists have been around for a long time, there is a reasonably high degree of certainty about the general costs. However, it should be noted that available evidence comes from a survey of experts. | ||
Cost effectivenessDoes the cost-effectiveness of the intervention favor the intervention or the comparison? | ||
Judgement | Research evidence | Additional considerations |
Using German data on costs, Titulaer et al. estimated that LTRA were associated with 31.7 Euro per one unit of symptom score improved. This value is higher than those observed for oral antihistamines (cetirizine: 18.3 Euro per one unit of symptom score improved) [1]. We were not able to use data from the MASK-air® app, as we had only 17 days of LTRA use in monotherapy and in which VAS-EQ5D data were provided (the number of days for which utility data has been provided is even lower). References Titulaer J et al. Cost-effectiveness of allergic rhinitis treatment: An exploratory study. SAGE Open Med. 2018;6. doi: 10.1177/2050312118794588 | ||
EquityWhat would be the impact on health equity? | ||
Judgement | Research evidence | Additional considerations |
We conducted a survey, having received responses from specialists from 51 countries (mostly in Europe, America and Asia). At least one OAH and one LTRA was reported to be available in all 51 countries. Other equity-related aspects  | ||
AcceptabilityIs the intervention acceptable to key stakeholders? | ||
Judgement | Research evidence | Additional considerations |
Satisfaction Evidence from direct patient data: In the MASK-air dataset, there were 7679 days in which OAH were used in monotherapy and for which patients provided information on how satisfied they were with their treatments. The median results of the visual analogue scale were of 84 (higher values indicating higher satisfaction) [IQR=30]. This compares to a median value of 94 for LTRA in monotherapy [IQR=10]. However, only 337 days were provided in relation to LTRA. Compliance 4 publications presenting data on acceptability were identified. [Kardas 2013, Koberlain 2013, Belhassen 2022, Szilasi 2012]. All studies were performed in North America or Europe. In the study assessing e-prescriptions for orally administered antihistamines, among the 2280 prescriptions, 1803 (79.1%) were redeemed – the rate of initial non-adherence amounted to 21%. The highest non-adherence (31.3%) was observed in the age group 19 – 39 years, while the highest adherence (84.6%) rate was observed in 75 and older patients. [Kardas 2013] In the post-marketing surveillance study with a total of 42,111 patients taking OAH, the physician graded compliance on a 4-point scale. Compliance was rated by questioning the patient whether the medication had been taken as instructed. During mean treatment duration of 41.6 days, 74.5% and 23.6% of the participants of the model group were “excellent” and “good” in terms of compliance with the intake of the H1-antihistamine. Only 1.6% and 0.3% had a “moderate” and “poor” compliance. [Koberlein 2013] Data from a study involving 3654 French patients with both allergic rhinitis and asthma also suggest a pattern of selective patient acquisition and limited compliance with GP prescriptions. The mean time interval between successive prescriptions was 97 days for antihistamines. On average, individual prescriptions resulted in 1.6 dispensations of antihistamines – patients regularly visited their GPs but irregularly obtained the prescribed therapy. [Belhassen 2022] On the other hand, the fact that LTRA can be used both for rhinitis and asthma may increase the compliance to this drug class in patients with both conditions. However, the occurrence of adverse effects – particularly neuropsychiatric ones – can result in discontinuation. Concerns with such adverse events can also result in lower compliance. Adherence One publication presenting data on Hungarian patients’ treatment adherence was identified. [Szilasi 2012]. The optimal adherence regarding antihistamine tablets was reported to be as low as 64.32% for mild and 60.19% for moderate-severe AR patients. Evaluating the possible causes of non-adherence the following were identified: 39.68% of mild AR and 31.49% of moderate-severe AR patients were without symptoms, thus they did not take the tablets. The second most frequent reason of nonadherence with oral treatment was forgetting to take it: this was recorded in 40.48% and 35.91% of mild and moderate/severe AR patients, respectively. Evidence from direct patient data: In complete weeks of MASK-air reporting during the pollen season, there were 38.5% of them in which OAH were used for 6 or 7 days. The number of weeks for LTRA users was insufficient (n=9) to allow for a comparison. Switching rate Evidence from direct patient data: In the MASK-air dataset, in 50.1% of the days in which OAH have been used, they have been used in comedication. This compares with 83.0% LTRA. In 4.1% of days with oral antihistamine use, more than one OAH was used (that is, patients tried at least two OAH on the same day). This compares to 0.4% of days with LTRA use. Onset of action In a rapid review of the literature, the median (min-max) onset of action of OAH was found to be 60 min (1 hrs) [15-150 min (0.25-2.5 hrs)] for improvement in nasal symptoms; and 120 min (2 hrs) [75-120 min (1.25-2 hrs)] for improvement in ocular symptoms. For LTRA, Donnelly et al reported the onset of action of LTRA to be lower than two hours [Donnelly]. References: 1. Kardas G, Panek M, Kuna P, Cieszyński J, Kardas P. Primary Non-Adherence to Antihistamines-Conclusions From E-Prescription Pilot Data in Poland. Front Pharmacol. 2020 May 21;11:783. doi: 10.3389/fphar.2020.00783. PMID: 32528297; PMCID: PMC7253696. 2. Köberlein J, Kothe AC, Sieber J, Mösges R. Determining factors of patient compliance to treatment in allergic rhinitis. Asian Pac J Allergy Immunol. 2013 Jun;31(2):148-56. doi: 10.12932/AP0264.31.2.2013. PMID: 23859415. 3. Belhassen M, Bérard M, Devouassoux G, Dalon F, Bousquet J, Van Ganse E. Treatment of Allergic Rhinitis and Asthma in Primary Care: Dispensations Do Not Align with Prescriptions. J Asthma Allergy. 2022 Nov 25;15:1721-1729. doi: 10.2147/JAA.S376786. PMID: 36457994; PMCID: PMC9707385. 4. Szilasi, M., Gálffy, G., Fónay, K. et al. A survey of the burden of allergic rhinitis in Hungary from a specialist’s perspective. Multidiscip Respir Med 7, 49 (2012). https://doi.org/10.1186/2049-6958-7-49 5. Donnelly AL, et al. The leukotriene D4-receptor antagonist, ICI 204,219, relieves symptoms of acute seasonal allergic rhinitis. Am J Resp Crit Care Med. 1995;151(6):1734-9. | ||
FeasibilityIs the intervention feasible to implement? | ||
Judgement | Research evidence | Additional considerations |
We identified one study that provides data on Safety-related barriers [1], that assessed the knowledge, attitudes, and practices of primary health care practitioners (PHCPs) towards allergic rhinitis guidelines in Saudi Arabia. Most PHCPs (82.6%) considered oral second‑generation antihistamines to be the safest medication for AR. In case of first generation OHA, only 59,9% of PHC physicians considered them as safe medication for AR. On the other hand, we did not identify any studies that adequately addressed the feasibility of leukotriene receptor antagonists. However, there have been studies indirectly providing some considerations about feasibility. Such considerations concern aspects such as (i) costs (which tend to be higher than those observed for other drug classes), (ii) perceived risk of adverse events (particularly neuropsychiatric ones), and patient preference of oral medications over nasal ones [2,3]. References: 1. Almousa H, Alsaad SM, Ismail D, Mahjoub S, Bin Obaid S, Alsaleh S. Allergic rhinitis guidelines knowledge, attitudes, and practices among primary health care physicians: A national multicentre cross-sectional study. J Family Med Prim Care. 2023 Jun;12(6):1202-1208. doi: 10.4103/jfmpc.jfmpc_85_23. Epub 2023 Jun 30. PMID: 37636198; PMCID: PMC10451594. 2. Titulaer J et al. Cost-effectiveness of allergic rhinitis treatment: An exploratory study. SAGE Open Med. 2018;6. doi: 10.1177/2050312118794588 Erdem SB, Nacaroğlu HT, Can D. Adverse drug reactions affecting treatment adherence in first-line treatment of asthma: An observational study. Allergol Immunopathol (Madr). 2023;51(2):11–6. | ||
Planetary healthWhat would be the impact on planetary health? | ||
Judgement | Research evidence | Additional considerations |
We did not identify any studies that satisfactorily investigated OAH compared with LTRA in terms of planetary health. The manufacturer life cycle assessment internal report indicated that montelukast was responsible for 0.23-0.47 kg CO2e/product [1]. However, such information was not available for OAH. Key considerations include the availability of locally produced medications, as well as medication effectiveness in reducing healthcare resource utilization. References: 1. Busby J, Khezrian M, Patel S, et al. Exploring the carbon footprint of severe asthma and change after biologic therapy initiation: an analysis of Northern Irish data. ERJ Open Res. 2025 Jun 23;11(3):01009-2024. doi: 10.1183/23120541.01009-2024 | ||
Summary of judgements
Judgement | |||||||
|---|---|---|---|---|---|---|---|
Problem | No | Probably no | Probably yes | Yes | Varies | Don’t know | |
Desirable Effects | Trivial | Small | Moderate | Large | Varies | Don’t know | |
Undesirable Effects | Trivial | Small | Moderate | Large | Varies | Don’t know | |
Certainty of evidence | Very low | Low | Moderate | High | No included studies | ||
Values | Important uncertainty or variability | Possibly important uncertainty or variability | Probably no important uncertainty or variability | No important uncertainty or variability | |||
Balance of effects | Favors the comparison | Probably favors the comparison | Does not favor either the intervention or the comparison | Probably favors the intervention | Favors the intervention | Varies | Don’t know |
Resources required | Large costs | Moderate costs | Negligible costs and savings | Moderate savings | Large savings | Varies | Don’t know |
Certainty of evidence of required resources | Very low | Low | Moderate | High | No included studies | ||
Cost effectiveness | Favors the comparison | Probably favors the comparison | Does not favor either the intervention or the comparison | Probably favors the intervention | Favors the intervention | Varies | No included studies |
Equity | Reduced | Probably reduced | Probably no impact | Probably increased | Increased | Varies | Don’t know |
Acceptability | No | Probably no | Probably yes | Yes | Varies | Don’t know | |
Feasibility | No | Probably no | Probably yes | Yes | Varies | Don’t know | |
Planetary health | Reduced | Probably reduced | Probably no impact | Probably increased | Increased | Varies | Don’t know |
Type of recommendation
Conclusions
Recommendation |
In adults with allergic rhinitis, the ARIA guideline panel recommends using oral antihistamines over leukotriene receptor antagonists (strong recommendation based on moderate certainty of evidence). |
Justification |
The decision is mostly grounded on the fact that oral antihistamines are associated with less safety concerns, are more affordable, are associated with less equity-related concerns and tend to be associated with high acceptability. In addition, oral antihistamines tend to be more efficacious than leukotriene receptor antagonists, even though such difference is mostly trivial. |
Subgroup considerations |
For preschool and school children, the ARIA guideline panel recommends using oral antihistamines over leukotriene receptor antagonists. |
Implementation considerations |
None specific |
Monitoring and evaluation |
Research priorities |
Research priorities by domain of the certainty of evidence assessment:
EtD criteria for which research is most needed: In addition to primary studies focused on the desirable and undesirable effects of ocular antihistamines versus leukotriene receptor antagonists (considering the gaps described above), new studies are needed on the following criteria:
|