Efficacy of mometasone furoate nasal spray in the treatment of allergic rhinitis. Meta-analysis of randomized, double-blind, placebo-controlled, clinical trials


Prof. Giorgio Walter Canonica
Allergy and Respiratory Diseases
Padiglione Maragliano
L.go R. Benzi 10
Genoa 16132


Rationale:  Several randomized, double-blind, placebo-controlled clinical trials have demonstrated the efficacy of mometasone furoate nasal spray (MFNS) in the treatment of allergic rhinitis (AR) thus allowing for a meta-analysis to determine the overall treatment effect.

Methods:  A comprehensive search of the MEDLINE, LILACS, SCOPUS, and the Cochrane Library databases up to 31 October, 2007 was carried out. Randomized, double-blind, placebo-controlled, clinical trials evaluating the efficacy of MFNS in patients with AR compared to placebo were included. Total nasal symptom scores (TNSS), individual nasal symptoms, total non-nasal symptom scores (TNNSS) and nasal airflow were analysed as the standardized mean difference (SMD). Meta-analysis was performed with the random or the fixed effect models depending on heterogeneity, by using revman 5 software.

Data synthesis:  Sixteen of the 113 identified articles met the inclusion criteria. For MFNS efficacy on TNSS, 2998 participants were analysed: 1534 received MFNS and 1464 placebo. Mometasone furoate nasal spray was associated with a significant reduction in TNSS (SMD −0.49, 95% CI: −0.60 to −0.38; P < 0.00001; I2 = 50.1%). A significant effect on SMD for nasal stuffiness/congestion (−0.41; 95% CI: −0.56 to −0.27), rhinorrhoea (−0.44; 95% CI: −0.66 to −0.21), sneezing (−0.40; 95% CI: −0.57 to −0.23) and nasal itching (−0.39; 95% CI: −0.53 to −0.25) was also demonstrated. Mometasone furoate nasal spray treated subjects also showed a significant reduction in TNNSS (−0.30; 95% CI: −0.43 to −0.18). The proportion of patients with adverse events was similar for MFNS and placebo (0.99; 95% CI: 0.81–1.20; P = 0.91).

Conclusions:  This meta-analysis provides a level Ia evidence for the efficacy of MFSN in the treatment of AR vs placebo. Adverse events frequency was similar in both groups.

The prevalence of allergic rhinitis (AR) has increased over the past decade. Recent data suggest that 5–40% of adults and up to 45% of children in some countries are affected (1–3). In recent years, the better knowledge of the mechanisms of the disease and the availability of effective new treatments has remarkably improved the strategy of management of the disease. Optimal therapy aims not only to achieve symptomatic relief, but also to control the underlying inflammatory process that is the main cause of the bothersome nasal obstruction. Indeed, the beneficial effect of treatments on each of the symptoms can vary according to the mode of action of the drug (4–8).

Nasal corticosteroids are recommended as first line therapy, especially for patients with moderate-to-severe or perennial symptoms and when nasal obstruction is a major concern (8–11). Mometasone furoate, a potent, topically active, synthetic, 17-heterocyclic corticosteroid was originally introduced for the treatment of dermatological conditions (12). Subsequently, mometasone furoate aqueous nasal spray (MFNS) (Nasonex; Schering-Plough, Inc., Kenilworth, NJ, USA) was shown to be effective in several inflammatory conditions of the upper respiratory tract, including AR (4) and non-AR (12), nasal polyps (13, 14), adenoidal hypertrophy (15) and uncomplicated rhinosinusitis (16).

During the last years, several randomized, double-blind, placebo-controlled, clinical trials (RCT DB PC) assessing the efficacy of MFNS in adults and children with AR have been published (4, 17). Clinical data overall show that MFNS is effective not only in treating the symptoms of seasonal AR (SAR; 18, 19), but also in preventing the onset of symptoms in such patients (20). Furthermore, MFNS has proven efficacy for the sustained treatment of perennial AR (PAR; 4, 21).

Safety and pharmacokinetic evaluations of MFNS have shown a lack of systemic activity when applied to the nasal mucosa, even in pediatric patients (22). There is no clinical evidence that MFNS suppresses the function of the hypothalamic–pituitary–adrenal axis when the drug is administered at clinically relevant doses (100–400 μg/day) (14, 23), and there are no reports of any influence on children’s growth (24–26). Finally, histological studies after long-term use of MFNS have shown no signs of atrophy of the nasal mucosa (27).

The aim of this review was to assess the overall efficacy of MFNS for the treatment of AR in the context of RCT DB PC by means of the meta-analysis approach.


Search strategy

This review was conducted following the Cochrane Collaboration and the QUOROM guideline standards (28, 29). Four electronic databases (MEDLINE, LILACS, SCOPUS and the Cochrane Library) were searched from 1966 to 31 October, 2007, for RCT DB PC that evaluated the efficacy of MFNS in patients with AR, with MeSH headings and text words. We looked also for any additional studies mentioned in the references of identified publications, including previous narrative reviews. Abstracts of relevant meetings were also searched.

Two authors conducted independent search strategies. The first MEDLINE search strategy retrieved citations containing the subject heading mometasone (limited to the publication types: clinical trial and meta-analysis) or the text words nasal steroids, topical corticosteroids, active metabolite or Nasonex®. The second MEDLINE search strategy retrieved citations containing the subject heading mometasone combined with exploded subject headings describing allergic disease (rhinitis, hay fever, rhinoconjunctivitis) or text words describing the efficacy of MFNS in AR appearing in close proximity (mometasone, allergy, rhinitis, efficacy) or those focused to the target population (humans). We limited citations from the second search to RCT using a maximally sensitive strategy (30). We modified these searches for other databases. We screened reference lists from all retrieved articles and from recent review articles to identify additional studies. There were no language restrictions.

Study selection and characteristics

Only randomized, placebo-controlled and double-blinded clinical trials were included. Patients had to have a history of AR with or without allergic asthma and/or conjunctivitis, in which the causal allergen was identified and IgE sensitization was proven by prick test and/or specific IgE assays. All MFNS doses and all treatment durations were considered. Postchallenge studies were included, but these were the subject of an individual sub-analysis. Trial eligibility was determined from the full text format of the retrieved study by two investigators and checked by the investigator in chief. The observed percentage agreement between the investigators for the assessment of inclusion was calculated by using the κ-test (29, 31). The κ statistic represents the rate of agreement between two independent observers remaining after chance agreement is removed. Kappa ranges from 1 (excellent) to 0 (no agreement) (32).

Assessment of validity

Methodological information relevant to the assessment of internal validity consisted of: method of allocation, generation and concealment of randomization, blinding of caregivers/outcome assessors, number of and reasons for withdrawals. Quality of trials was quantified in duplicate using the Jadad scale (33, 34) that scores from 0 (lower quality) to 5 (excellent quality) (Table 1). Inter-rater agreement was calculated by using the κ statistic (29, 31, 32).

Table 1.   Characteristics of studies and participants
ReferenceParticipantsStudy designTreatment
  1. RCTDB, randomized clinical trial, double-blind; BDP, beclomethasone dipropionate aqueous nasal spray; FP, fluticasone propionate; BANS, budesonide aqueous nasal spray.

  2. *Jadad score.

  3. †Postdropout: available data for analysis. Comparisons MFSN vs placebo.

Age (years)Disease classification by authorsDisease severityStudy design Quality score*Comparisons other than placebo (μg)Subjects included in analysis†MFNSPlacebo Dropout rate (%) Dose (μg)FrequencyDuration (weeks)
J Allergy Clin Immunol
36SeasonalModerate to severeRCT DB5/5BDP 3362151141010.6200OD8
Ann Allergy Asthma Immunol
38SeasonalModerate to severeRCT DB5/5MFNS 50, 100, 800189969511200OD4
Ann Allergy Asthma Immunol
32PerennialAll gradesRCT DB5/5BANS 128, 2562071031048200OD4
Ann Allergy Asthma Immunol
34PerennialModerate to severeRCT DB
5/5FP 20036518118414200OD12
Ann Allergy Asthma Immunol
33PerennialModerate to severeRCT DB
5/5BDP 40025312912423200OD12
31SeasonalModerate to severeRCT DB5/5Only placebo200101992200OD2
J Allergy Clin Immunol
12–65SeasonalAll gradesRCT DB4/5Only placebo12180415200OD2
J Allergy Clin Immunol
9SeasonalAll gradesRCT DB4/5MFNS 25, 200; BDP 1682711351365100OD4
48.4PersistentAll gradesRCT DB
4/5Only placebo2020205200OD4
27.3SeasonalAll gradesRCT DB4/5Only placebo2413110200OD2
33SeasonalModerate to severeRCT DB
5/5MFNS 100; BDP 4002321221105200OD4
Ann Allergy Asthma Immunol
34.7SeasonalModerateRCT DB4/5Only placebo2451221232200OD2
Ann Allergy Asthma Immunol
33SeasonalAll gradesRCT DB4/5Only placebo209110200OD2
Ann Allergy Asthma Immunol
40.1SeasonalAll gradesRCT DB
4/5Only placebo2121210200OD2
Allergy Asthma Proc
33.9SeasonalModerate to severeRCT DB4/5Only placebo2351191161.7200ODSingle dose
Am J Rhinol
37SeasonalModerate to severeRCT DB4/5Azelastine 5483001501500200ODSingle dose

Data extraction

Two independent reviewers extracted data from the selected articles, reconciling differences by consensus. Observer variation for continuous data was quantified and plotted using the Bland & Altman test (35, 36). We planned an intention-to-treat analysis (ITT) and we tried to include dropouts in the analysis if last observation carried forward (LOCF) for continuous scores was available; if not, we just included subjects with a final assessment. When data were not accessible in papers, authors were contacted and the requested data were provided by them. In the case of missing SD, values were obtained from both mean differences and P-values, following The Cochrane Collaboration recommendations (29). When the results were only presented in graphs, these were digitized and then converted to numbers using the plot digitizer 2.4.1 program (37).

Data synthesis

The following outcomes were investigated: total nasal symptom scores (TNSS), nasal individual symptom scores (congestion, rhinorrhoea, sneezing and nasal itching), non-nasal symptom scores (ocular, otic, palate and throat complaints, cough, etc.) (38), nasal airflow and adverse events frequency. In the original studies, different scoring systems and scales were used to evaluate symptoms (usually a daily assessment of symptoms recorded on a diary and subsequently summarized and averaged). The investigators of each trial provided post-treatment mean and SD values for both the active treatment and placebo groups. As continuous outcomes were measured and expressed in different scales, we used the standardized mean difference (SMD) (29, 39, 40). Dichotomous outcomes were analysed with odds ratios (adverse effects frequency) (29). Heterogeneity was calculated with the Cochran’s Q statistic test and the I-square test (I2). I-square test describes the rate of variation across studies because of heterogeneity rather than chance and ranges from 0 (no heterogeneity) to 100 (maximum heterogeneity) (39, 41, 42). All results are reported with 95% confidence intervals (95% CI) and all P-values are two-tailed.

When a significant heterogeneity among the outcomes analysed was found (I2 > 50), the random-effects model (REM) according to Dersimonian–Laird was used. This model assumes that the true treatment effects in the individual studies may be different from one another and that these are normally distributed (42–44). We explored this effect-size distribution with QQ plots and histograms. The QQ plots compare the quantiles of an observed distribution against the quantiles of the standard normal distribution. In a meta-analysis, such a plot can be used to check the normality assumption, investigate whether all studies come from a single population and search for publication bias (45). Those outcomes that did not present with heterogeneity (I2 < 50) were analysed with the fixed-effects model (FEM). Fixed-effects model uses the inverse variance approach and it is assumed that all studies come from a common population (29, 40). Details about statistical methods used in this review were previously published (46). Analysis was performed using revman 5 program (The Cochrane Collaboration, Oxford, UK) (47) and spss 14.0 for Windows (SPSS Inc, Chicago, IL, USA) (48).

Data synthesis

Search results

The primary search identified up to 242 articles, 113 of which were potentially relevant trials on MFNS in the treatment of AR (Fig. 1).

Figure 1.

 Handling of trials identified through study search.

Sixteen articles met the mentioned inclusion criteria for meta-analysis (17–21, 24, 49–58). κ statistic for inter-rater agreement on study eligibility was 0.90 (95% CI: 0.80–1.0). Consensus was reached on the remaining trials. Some randomized trials were excluded from the review for the following reasons: 11 were open or single-blind evaluations, seven did not compare MFNS with placebo, one did not have suitable data and one was a duplicate (Fig. 1).

Trial characteristics

Table 1 summarizes the characteristics of the studies and subjects included in this review. We included in the meta-analysis MFNS- or placebo-treated subjects. For those studies evaluating more than one MFNS dosage, we selected out the group receiving 200 μg/day for adults and 100 μg/day for children. According to that, 2998 participants who had a final clinical assessment were analysed from 16 RCT. One study included both postintervention and postnasal challenge measurements (17). Consequently, 17 evaluations on TNSS were included (10 interventional studies comparing MFNS vs placebo for the treatment of AR in 1878 adults (17–19, 21, 49–54); one RCT evaluating 271 children (24); five studies assessing postchallenge effects on TNSS in 634 participants (17, 55–58) and one study commenced treatment 4 weeks preseasonally (n = 215) (20). Data on the individual nasal symptom scores were available in seven studies including 1582 subjects (19, 21, 49–52, 54). Non-nasal symptom scores were assessed in four studies (n = 1009) (21, 49, 51, 52) and nasal airflow in three studies (n = 271) (17, 50, 53). The frequency of adverse events (AE) was available in nine trials (n = 2072) (17, 18, 20, 21, 24, 49, 51, 52, 54).

The age range of participants was 5–65 years. Each trial included a median of 211 participants (range 20–365); 109 for MFNS (range 9–181) and 103 for placebo (range 11–184). Twelve studies included patients with SAR (18–20, 24, 49, 52–58) and four with PAR (17, 21, 50, 51). The median for MFNS and placebo administration was 3 weeks: two studies provided interventions as single dose (57, 58), six during 2 weeks (19, 52–56), five for 4 (17, 18, 24, 49, 50), one during 8 (20) and two for 12 weeks (21, 51). Main comparisons were made using 200 μg of MFNS (15/16 trials). Six studies compared the efficacy of MFNS and placebo with diverse doses of nasal steroids (18, 20, 21, 24, 50, 51) and one vs azelastine (57). All authors gave MFNS once a day (Table 1).

Methodological quality of included studies

All the trials were randomized and DB PC. Eleven evaluated parallel groups, three used a double-dummy design and two were cross-over. Each trial reported dropouts, withdrawals and patients completing the trial; dropout rate varied between 0% and 23%. Based on Jadad’s criteria, seven studies received a 5/5 quality score and nine studies 4/5. The κ score for inter-rater agreement on methodological quality was 0.95 (95% CI: 0.90–1.0) (Table 1). When effect-sizes distribution with QQ plots and histograms were explored, we found the studies had different study-specific effects, but these followed a normal distribution (45).

Data extraction

Data were available in the full text version of five papers (19, 24, 50, 55, 57); authors or associate investigators of six studies provided SD and/or means (21, 49, 51–54); in five studies, means were available, but SD were obtained from both mean differences and P-values following the Cochrane Collaboration guidelines (17, 18, 20, 56, 58).


Total nasal symptom scores.  Ten RCT assessed the efficacy of MFNS as treatment of AR in adults (17–19, 21, 49–54). Out of the 1878 participants, 967 received MFNS 200 μg and 911 placebo. Mometasone furoate nasal spray induced a significant reduction in TNSS compared with placebo (SMD −0.56, 95% CI: −0.71 to −0.41; P < 0.00001). A significant inter-study heterogeneity was found (χ2 = 21.46, P = 0.01; I2 = 58%) Five studies assessed the postchallenge effect of the interventions: 318 subjects received MFNS 200 μg and 316 received placebo (17, 55–58). Those treated with MFNS had a significant decrease in symptoms (SMD −0.33, 95% CI: −0.50 to −0.17; P < 0.0001). In this sub-analysis, heterogeneity was low (I2 = 6%). In the study carried out in children (135 received MFNS 100 μg/and 136 placebo), those treated with MFNS showed a significant reduction in nasal symptoms (SMD −0.41, 95% CI: −0.65 to −0.17; P = 0.0008) (24). In the RCT conducted by Graft et al. (20), subjects were preseasonally treated during 4 weeks and then for 4 weeks more (114 MFNS and 101 placebo). Those receiving MFNS showed lower TNSS (SMD −0.35, 95% CI: −0.62 to −0.08; P = 0.01) (20) (Fig. 2).

Figure 2.

 Outcome: total nasal symptom scores.

Individual nasal symptom scores.  Data were available in seven studies (812 participants treated with MFNS and 770 with placebo) (19, 21, 49–52, 54). A significant reduction in SMD for nasal stuffiness/congestion (SMD −0.41; 95% CI: −0.56 to −0.27; P < 0.00001), rhinorrhoea (SMD −0.44; 95% CI: −0.66 to −0.21; P = 0.0001), sneezing (SMD −0.40; 95% CI: −0.57 to −0.23; P < 0.00001) and nasal itching (SMD −0.39; 95% CI: −0.53 to −0.25; P < 0.00001) was found in subjects received MFNS 200 μg. Heterogeneity was significant in all these sub-analyses but nasal itching (51%, 79%, 64% and 48%, respectively) (Fig. 3).

Figure 3.

 Outcome: individual nasal symptom scores.

Non-nasal symptom scores.  These were reported by four authors (21, 49, 51, 52). Five-hundred and seven participants received MFNS 200 μg and 502 placebo; in those treated with MFNS 200 μg a significant reduction in SMD was observed (SMD −0.30, 95% CI: −0.43 to −0.18; P < 0.00001). Heterogeneity was not significant (I2 = 34%); then, analysis was performed with the FEM (Fig. 4).

Figure 4.

 Outcome: non-nasal symptom scores.

Nasal airflow.  Two studies assessed the peak nasal inspiratory flow (17, 50) and one the nasal flow (53). All three studies demonstrated an increase in the nasal flow of MFNS treated patients compared with those received placebo (SMD 0.32; 95% CI: 0.08–0.56; P = 0.01; I2 = 33%). Nonetheless, because of different methods of air flow measurement and the paucity of subjects evaluated, this outcome was not considered for the paper conclusions to avoid bias.

Adverse events.  Nine trials reported the occurrence of adverse reactions (1041 MFNS/1031 placebo). The proportion of patients with adverse events was similar for MFNS and placebo (OR = 0.99; 95% CI: 0.81–1.20; P = 0.91). Heterogeneity was not significant (17, 18, 20, 21, 24, 49, 51, 52, 54) (Fig. 5).

Figure 5.

 Outcome: adverse events.

Sensitivity analyses. Post hoc analysis of trials subsets evaluating treatment duration, AR classification, model for studies weight determination and methods for data extraction showed that none of them substantially changed the overall significance for TNSS (Table 2).

Table 2. Post hoc sensitivity analyses
OutcomeStudies (n)*Subjects (n)I2 (%)EffectCI 95%P-value
  1. REM, random effects model; FEM, fixed effects model; SD, standard deviation; TNSS, total nasal symptom score.

  2. *Only studies evaluating the efficacy of MFNS as a treatment for allergic rhinitis were included in this analysis (18–21, 24, 49–54).

TNSS: seasonal allergic rhinitis*6101362.9−0.52−0.74 to −0.30< 0.00001
TNSS: perennial allergic rhinitis*486550.8−0.62−0.83 to −0.41< 0.00001
TNSS: treatment duration: 2 weeks*459073.6−0.57−0.93 to −0.210.002
TNSS: treatment duration: ≥ 4 weeks*6128847.8−0.56−0.68 to −0.45< 0.00001
TNSS evaluated with the REM17299850.1−0.49−0.60 to −0.38< 0.00001
TNSS evaluated with the FEM17299850.1−0.47−0.54 to −0.40< 0.00001
TNSS: only trials where SD were provided by author or extracted from full text article12243260.7−0.51−0.64 to −0.37< 0.00001

Implications for research

Further long-term evaluations of MFNS efficacy and safety should be conducted in the context of RCT DB PC, in patients with PAR. Also, additional assessments about MFNS effect on airflow are required.

Implications for practice

This study, using well accepted meta-analysis methodology, provides significant evidence that treatment with MFNS 200 μg, once daily is effective in relieving symptom scores of both SAR and PAR.


Meta-analysis is a statistical procedure that incorporates the results of different independent studies pooled together, thus allowing a more objective and robust appraisal of the evidence than traditional narrative reviews can do. Meta analyses provide a quantitative estimate of treatment effects, and may explain and quantify the heterogeneity among individual studies (29, 40, 42, 43). To warrant their quality, strategies, standards and recommendations have been developed, such as the quality of reporting of meta-analyses (QUOROM) (28).

This meta-analysis of RCT DB PC clearly demonstrates that MFNS 200 μg, once daily is effective in relieving symptoms scores of both SAR and PAR, thus further supporting current recommendations. Our review included 16 studies out of the 242 identified through our search, and we were able to evaluate 2998 participants for the effect of the intervention. In this regard, we selected out only those trials conducted with a rigorous methodology to provide solid conclusions. Thus, the selection of trials had to be, necessarily, very restrictive. Indeed, meta-analyses often include small numbers of studies and heterogeneity is therefore a consequence (59).

In this meta-analysis, we analysed data from different published clinical trials involving patients with PAR or SAR, treated with the recommended dose and from short-term challenge studies. Even though there was a variable degree of heterogeneity among studies, MFNS had an overall beneficial effect on the symptoms of AR, as measured by total and individual symptoms scores. Mometasone furoate nasal spray efficacy was consistently significant compared to placebo when treatment duration, rhinitis classification or statistical methods were stratified. Also, we found that effect sizes and their 95% CI were similar for those studies evaluating SAR and PAR, though the numbers of studies evaluating subjects with PAR was limited (Table 2). For those studies evaluating TNSS postnasal challenges, reduction on this outcome was significant but it was considered lower than those observed when MFNS was used as treatment (Fig. 2).

Three studies compared different MFNS doses in patients with SAR. Bronsky et al. (49), randomized 840 adults to receive MFNS 50, 100, 200 or 800 μg or placebo once daily for 28 days. The 50 μg dose and the 100 μg dose showed less consistent activity at early time-points (days 3 and 7), while the 800-μg dose did not provide significant additional benefits over the 200-μg dose. Hebert et al. (18) compared MFNS 100, 200 μg once daily, beclomethasone dipropionate (BDP) 400 μg/day and placebo for up to 4 weeks. At the end of treatment, complete or marked relief was obtained in 77% of patients with MFNS 100 μg/day, 79% with 200, and 74% with BDP, compared with 54% of placebo vehicle control patients (18). In children, Meltzer et al. (24), randomized 679 children 6–11 years of age to MFNS 25, 100, 200 μg once daily, BDP 84 μg twice daily (168 μg/day) or placebo. Reductions for nasal symptom scores were significantly greater in the MFNS and BDP groups than in the placebo group (P = 0.02) MFNS 100 and 200 mg once daily both were significantly more effective than MFNS 25 mg once daily in relieving symptoms of AR, but MFNS 200 mg provided no additional benefit over MFNS 100 mg. In all the above studies, the safety profile was quite satisfactory.

All individual nasal symptoms were reduced in patients receiving MFNS, and this was especially true for nasal congestion that is the most difficult symptom to treat. Evaluations of congestion scores demonstrated a significant reduction after treatment with MFNS 200 μg (SMD −0.41; 95% CI: −0.56 to −0.27; P < 0.00001) (9, 60, 61). A meta-analysis including 2267 subjects with AR with data obtained from 16 RCT compared the effects of oral antihistamines and nasal corticosteroids. There was a significant benefit to nasal corticosteroids over antihistamines for nasal congestion (SMD −0.63; 95% CI: −0.73 to −0.53), and sneezing (−0.49, −0.59 to −0.39). In contrast, there was no significant difference between nasal corticosteroids and antihistamines in relieving ocular symptoms (61). Similar results were obtained in a meta-analysis of 648 subjects from nine studies comparing topical nasal antihistamines and nasal steroids (60).

When therapy combination given to patients with PAR has been evaluated, it was demonstrated that a topical corticosteroid can further reduce nasal symptoms when it is added to an antihistamine (62). Conversely, large double-blind studies have failed to show increased efficacy on nasal symptoms when an antihistamine is given to patients on a topical corticosteroid (61, 63).

In this review, subjects treated with MFNS showed a significant reduction in non-nasal symptom scores compared with those receiving placebo. Similar findings have been described by other authors. In a preliminary report by Sussman et al. (64), they found that MFNS 200 μg/day was effective in reducing symptoms scores in patients with moderate to severe ocular symptoms of SAR. In the study by Gawchik et al. (54), it was suggested that MFNS is potentially effective in treating the symptom of cough, which is commonly reported in AR and is thought to arise as a result of postnasal drip. In this RCT DB PC, 245 patients with at least a 1-year medical history of moderate SAR were randomized to receive MFNS 200 μg OD or placebo. Patients treated with MFNS showed a significant improvement in the severity of their daytime cough compared with those treated with placebo (P < 0.049) (54).

Nasal flow was described to increase increased in MFNS treated patients, but heterogeneity in methods of measurement might be a source of bias. Consequently, further evaluations about the effects of topical steroids on nasal flow should be conducted (29).

The frequency of AE in patients treated with MFNS was similar to those who received placebo. Results from pharmacokinetic studies in adults and children suggest that systemic exposure to MF after intranasal administration is negligible. This is probably because of its inherently low aqueous solubility, which allows only a small fraction of the drug to cross the nasal mucosa and enter the bloodstream, and because a large amount of the administered drug is swallowed and undergoes extensive first-pass metabolism (22). There is no clinical evidence that MFNS suppresses the function of the hypothalamic–pituitary–adrenal axis when the drug is administered at clinically relevant doses (100–400 μg/day) (14, 23). Furthermore, its safety and tolerability have been assessed in clinical trials involving approximately 4500 patients, with epistaxis, headache and pharyngitis being the most common adverse effects (22).

The present meta-analysis has several strengths, such as the restrictive inclusion criteria for the studies, the statistically significant effect size found according to Cohen’s criteria (65), the robust statistical methods to control both inter and intra study variability, and the quantitative approach carried out (29, 40, 58). Moreover, most of the analysed data were provided by the authors. All of the QUORUM requirements were eventually fulfilled in this review (28). On the other hand, we identified some possible bias sources (66). First, the degree of heterogeneity of the scores used to evaluate the outcomes was significant. Nonetheless, heterogeneity is not uncommon; about a quarter of meta-analyses have I2 values over 50% (59). To reduce this bias, we utilized some control measures, such as the SMD, which is a robust measure utilized to manage the outcome diversity. Moreover, to reduce the bias of inter-study heterogeneity, we used the REM (29, 40, 43, 44, 67) (Table 1). Secondly, individual patient data were not available from each of the studies to test normality. Using graphical methods, we found that effect sizes for symptom scores followed a normal distribution. Thirdly, it was not possible to carry out an ITT analysis, because LOCF for continuous scores was not always available; therefore, we analysed patients with a final assessment. In this way, an inaccurate global effect due to sample size overestimation was avoided. Finally, a large clinical trial about MFNS efficacy in AR was excluded from our analysis. This study pooled data obtained from four RCT DB PC using MFNS 200 μg once daily given over 2 weeks in patients with SAR. Significant improvements in mean nasal congestion score were seen with MFNS [reduction 27% (n = 490) vs placebo 13% (n = 492); P < 0.001]. However, because of its design, this was not comparable with the other studies; consequently, this was not analysed (68).

Publication bias is an important drawback of systematic reviews and is difficult to avoid. Although we searched for articles in the most important electronic databases available, in abstract books from relevant meetings and in the most diffuse languages, it is possible that not all the studies have been found (30, 69). Nonetheless, by means of funnel plot analysis, a bias source was not evident in this sample of studies (70) (Fig. 6). Concerning the quality of the studies included, it was good overall (all studies had a Jadad’s score above 4/5), although some methodological deficiencies in some trials could be noticed, such as the limited sample size.

Figure 6.

 Funnel plot assessing publication bias. Total nasal symptom scores.

In conclusion, the results of this meta-analysis demonstrate that MFNS is effective in reducing both total and individual symptom scores in patients with AR, including nasal congestion. Treatment with MFNS is also associated with improvements in non-nasal manifestations of the disease. This is the first evaluation that provides a level Ia evidence for the efficacy of a topic steroid in the treatment of AR vs placebo.


This study has been partially supported by ARMIA (Associazione per la Ricerca delle Malattie Immunologiche e Allergiche–Genova) and GA2LEN (The Global Allergy and Asthma European Network). We are thankful for the invaluable assistance and advice of Professor Humberto Diaz-Ponce. We really appreciate the unrestricted collaboration of Professors Eli O. Meltzer, Boris Stuck and Sandra Gawchik. We thank Marek Damašek for the graphic support.

Potential conflicts of interest

Professor Giorgio Walter Canonica and Professor Giovanni Passalacqua have received research grants and lecture fees from Alk-Abello, Anallergo, Allergy Therapeutics, A. Menarini, Almirall, Altana, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Genentech, Gentili, Glaxo Smith Kline, Lofarma, Merck Sharp & Dome, Novartis, Pfizer, Schering-Plough, Stallergenes and UCB Pharma. Dr Martin Penagos has received research grants from Aventis, Glaxo Smith Kline and Schering-Plough. Dr Enrico Compalati and Dr Francesco Tarantini have not declared conflicts of interest.