by Princy Mittal, Rajiv Mahajan and Kapil Gupta^[1], Adesh Institute of Medical Sciences & Research, Bathinda, India

 

Abstract

Objective

Seasonal allergic rhinitis is a common childhood problem affecting up to 40% of children. Many medications are available for use in the paediatric population; the present study evaluates the efficacy and tolerability of the leukotriene antagonist montelukast in seasonal allergic rhinitis in children aged 2-5 years.

Methods

An open-label, six-week study was carried out, incorporating 200 patients of seasonal allergic rhinitis aged 2-5 years who were given montelukast 4mg tablets orally once daily at night, during the spring season. The primary efficacy and tolerability end points were a change from the baseline in the total nasal symptom score (TNSS) and a modified treatment tolerability evaluation score (MTTES) respectively. Moreover, quality of life index (QOLI) and parents' satisfactory score were also recorded. During the treatment period, parents/guardians recorded the symptom/tolerability scores on diary cards twice daily (morning and evening).

Results

The study comprised a patient sample of 128 boys and 72 girls. At the end of the study, the mean decrease in TNSS was 28.8% (p<0.001) compared to the baseline. There was a non-significant (p>0.05) increase in MTTES. Only 3% of the patients (four boys and two girls) needed additional-drug treatment. Montelukast performed fairly on QOLI and parents' satisfactory score also.

Conclusion

Montelukast is well tolerated and provides improvements in daytime and night-time symptoms, as well as quality of life parameters, for children aged 2-5 years with seasonal allergic rhinitis.

Keywords: Allergic rhinitis, montelukast, efficacy, nasal congestion, treatment, children

 

Introduction

Allergic rhinitis is an inflammation of the nasal passages, usually associated with watery nasal discharge and itching of the nose and eyes. The symptoms typically occur in the nose and eyes and usually occur after exposure to dust, danders, or certain seasonal pollens in people that are allergic to these substances (USA Today, 2009). Onset of allergic rhinitis is common in childhood, adolescence, and early adult years, with a mean age of onset of 8-11 years, but allergic rhinitis may occur in persons of any age. In 80% of cases, allergic rhinitis develops by age 20 years. The prevalence of allergic rhinitis has been reported to be as high as 40% in children, subsequently decreasing with age. Allergic rhinitis is less common in the geriatric population (Sheikh and Najib, 2009a).

The impact of allergic rhinitis has reached epidemic proportions and, globally, is estimated to account for 100 million days of lost work each year, 28 million days of lost productivity and 1.5 million missed school days per year. Allergic rhinitis is responsible for 16.7 million physician office visits per year and results in 5.9 billion dollars annually in direct expenditures. Children with allergic rhinitis often experience increased shyness, anxiety and fatigue (Faber, 2006).

Among children in the 2-5 year age group, a greater percentage of those with allergic rhinitis have at least one asthma-related admission (0.96% versus 0.64%) or emergency department visit (0.79% versus 0.69%) than those without allergic rhinitis. There are more stays in or visits to hospitals, general hospitals, and tertiary care hospitals by children with allergic rhinitis (3.89%, 7.17%, and 3.04%, respectively) than by children without allergic rhinitis (2.16%, 3.23%, and 1.52%). On average, children with allergic rhinitis had 1.14 times more outpatient visits than those without allergic rhinitis (Kang et al., 2008). Allergic rhinitis can have an important negative impact on the quality of life in children, impairing their learning performance, reducing their ability to concentrate, and causing disturbed sleep patterns. A range of other disorders has also been linked to paediatric allergic rhinitis, including sinusitis, sleep apnoea, nasal polyposis, nasal collapse, hearing impairment, abnormal craniofacial development, and impaired cognitive functioning (Gelfand, 2005).

The goal of treatment is to reduce the allergy symptoms. Avoidance of the allergen or minimisation of contact with it is the best treatment (USA Today, 2009). Otherwise many medications like antihistaminics, mast cell stabilizers, decongestants and recently leukotriene antagonists have been approved for use in the paediatric population. Patients with intermittent symptoms are often treated adequately with oral antihistamines, decongestants, or both as needed. Regular use of an intranasal steroid spray may be more appropriate for patients with chronic symptoms (Sheikh and Najib, 2009b).

Cysteinyl leukotrienes (CysLTs) are endogenous mediators of inflammation and play an important role in allergic airway disease by stimulating bronchoconstriction, mucus production, mucosal oedema and inflammation, airway infiltration by eosinophils, and dendritic cell maturation that prepares for future allergic response. Montelukast inhibits these actions by blocking type 1 CysLT receptors found on immunocytes, smooth muscle and endothelium in the respiratory mucosa (Nayak and Langdon, 2007). Montelukast was first licensed in January 1998 for use in children over 6 years of age and adults. It was only in January 2001 that the license was extended to include children aged 2 to 5 years (UKMIPG, 2001). It was initially marketed to be used as a maintenance therapy for asthma, and subsequently it was found to be useful in allergic rhinitis also (Nayak and Langdon, 2007). The recommended dose of montelukast for children up to 5 years is a 4mg chewable tablet; for children 6-14 years, a 5mg chewable tablet; and for adults, a 10mg tablet once daily (Walia et al., 2006).

Until now, studies regarding the role of montelukast in allergic rhinitis are very few and studies regarding the role of montelukast in children aged 2-5 years in seasonal allergic rhinitis are rare. Keeping these facts in mind, the present study was designed to evaluate the efficacy and tolerability of montelukast in children aged 2-5 years with seasonal allergic rhinitis.

 

Materials and Methods

The present study was an open-label, single-arm, six-week study, which included two hundred patients of seasonal allergic rhinitis aged 2 to 5 years who had typical symptoms of allergic rhinitis, i.e. sneezing, nasal congestion, nasal itching, and rhinorrhea, with a history of exposure to allergens. The primary objective of the study was to evaluate the efficacy and tolerability of montelukast; secondary objectives were to evaluate the parents' satisfactory score for montelukast and to assess the effect of montelukast on quality of life. The study was approved by the Institutional Ethical Committee (IEC) and due consideration was given to medical ethics. It was included in the protocol that at any time, on review, if it was suspected that any patient was not responding to treatment, or that intolerable or unusual adverse affects were developing, that treatment would be immediately withdrawn.

Patients

Two hundred patients with seasonal allergic rhinitis, diagnosed symptomatically and by eosinophil count, reporting to the out-patient department of a tertiary teaching hospital were enrolled in the study based on certain inclusion and exclusion criteria and were followed up to six weeks.

Inclusion criteria

• Patients of rhinitis with a history of worsening symptoms after exposure to allergens in the spring season
• Patients aged 2 to 5 years

Exclusion criteria

• Patients with perennial or vasomotor allergic rhinitis
• Patients of other forms of rhinitis like infective rhinitis, common flu etc.
• Patients aged <2 years or > 5 years
• Patients with bleeding tendencies

Methods

A written informed consent was taken from parents/guardians of the study subjects. Patients were given montelukast 4mg dispersible tablets orally once daily at night, during the spring season. The primary efficacy and tolerability end points were a change from the baseline in the total nasal symptom score (TNSS) and modified treatment tolerability evaluation score (MTTES) respectively (Philip et al., 2002) at the end of the therapy. TNSS combined scores for rhinorrhea (runny nose), sneezing, itchy nose, and nasal congestion (blocked nasal cavities). Each symptom was measured on a 0-3 scale; i.e. 0=absent, 1=mild, 2=moderate and 3=severe symptoms. MTTES combined scores of treatment-induced vomiting, disinclination for meals and treatment-induced cough. Component tolerability symptoms were given scores on a 0-3 scale. The need to withdraw therapy and the need for additional medication was also measured.

Secondary end points evaluated for assessing the effectiveness and tolerability of montelukast were the parents' satisfactory score (0-3 scale) and Quality of life index (QOLI) computed from changes in the night-time sleep period (NTSP) and night-time awakenings (NTA) due to allergic rhinitis symptoms. Any additional adverse effect of the drug was also noted. During the treatment period, parents/guardians recorded the efficacy, tolerability and QOLI scores on diary cards twice daily, once in the morning and once in the evening. Parents' satisfactory score were recorded by the clinicians at the end of study period.

Statistical analysis

The collected data was pooled, and mean and standard deviation was calculated for each component symptom. A comparison was made between values obtained after completing the treatment with the baseline values. For statistical analysis, paired t-test and least square of means test were used (Ghosh, 2005). A 95% confidence interval was considered for statistical calculations, while applying least square of means formula.

 

Results

In the present study, out of a total of two hundred patients, one hundred and twenty eight patients were males (boys), meaning that 64% of the study subjects were males while 36% were females and this difference in sex distribution was highly significant.

There was a highly significant (p<0.001) decrease in total nasal symptom score (TNSS) as well as in the individual component scores i.e. rhinorrhea, sneezing, itchy nose and nasal congestion. Mean decrease in TNSS was -1.87±0.80 (28.8%) at the end of study, as compared to baseline. Rhinorrhea, sneezing, itchy nose and nasal congestion decreased by 32.3%, 32.7%, 28.8% and 22.4% respectively, at the end of study. All these reductions were highly significant (p<0.001) (Table 1).

Symptom Parameter	Mean values			Percentage change	P value
	Baseline	At end of therapy	Change
Rhinorrhea	1.67±0.79	1.13±0.75	-0.54±0.80	32.3%	P<0.001
Sneezing	1.50±0.86	1.01±0.78	-0.49±0.77	32.7%	P<0.001
Itchy nose	1.49±0.78	1.06±0.79	-0.43±0.88	28.8%	P<0.001
Nasal congestion	1.83±0.88	1.42±0.73	-0.41±0.98	22.4%	P<0.001
TNSS	6.48±0.90	4.62±0.64	-1.87±0.80	28.8%	P<0.001

^{Table 1: Change in component-score and TNSS at the end of therapy as compared to baseline}

 

Regarding modified treatment tolerability evaluation scores, there was a non-significant (p>0.05) rise in individual symptom scores as well as in the total MTTES. Total MTTES increased by only 0.07±0.55 (0.11%), from a pre-treatment mean value of 0.59±0.55 to a post-treatment value of 0.66±0.51 and this increase in total MTTES was non-significant (p=0.16). Increase in treatment-induced vomiting, disinclination for meals and cough were also non-significant (Table 2).
 

Symptom Parameter	Mean values			P value
	Baseline	At end of therapy	Change
Vomiting	0.25±0.63	0.27±0.54	0.02±0.60	P=0.36
Disinclination for meals	0.10±0.38	0.12±0.38	0.02±0.36	P=0.22
Cough	0.25±0.60	0.28±0.58	0.04±0.64	P=0.22
Total MTTES	0.59±0.55	0.66±0.51	0.07±0.55	P=0.16

_{Table 2: Change in component-score and MTTES at the end of therapy as compared to baseline}

When least square of means were computed, the results of TNSS and MTTES remained consistent with the ones calculated from the paired t-test (Table 3).
 

Parameter	Least square of means	95% confidence interval	P value
TNSS	-0.67	-0.56 to -0.78	P<0.001
MTTES	-0.65	0.070 to 0.076	p>0.05

^{Table 3: TNSS and MTTES as calculated by least square of means}

Vomiting was reported in 41 (20.5%) patients; 18 patients were having vomiting even before the commencement of therapy, due to disease or other reasons. This was labeled as 'background noise'. So, treatment-induced vomiting actually occurred in 23 (11.5%) patients, as calculated after removing the background noise. Similarly disinclination for food and cough was reported in 9.5% and 22.5% patients respectively, but treatment-induced disinclination for food and cough scaled down to 5% and 12% respectively, when background noise was removed. Irritation, agitation, increase in day time sleeping was not reported in any of the children (Table 4).
 

Symptom Parameter	No. of patients affected at the end of study	No. of patients affected at the end of study after removing background noise
Vomiting	41	23
Disinclination for meals	19	10
Cough	45	24

^{Table 4: Major reported adverse effects of Montelukast (Quantified)}

Therapy was not withdrawn from any patient at any stage of the treatment. Only 3% of patients (a total of six patients, four boys and two girls) required additional drugs. Four patients required only one additional drug, i.e. antihistaminic levocetirizine orally, while two patients required the addition of two or more drugs: oral levocetrizine and nebulized glucocorticoid budesonide were used for one patient, while oral levocetrizine and nebulized budesonide plus salbutamol combination was used for the second patient (due to the exacerbation of asthma in these patients).

Montelukast also performed fairly on secondary endpoints. Acceptance of montelukast by parents was good. It performed fairly on parents' satisfactory score by gaining a score of 65% (1.95 out of 3). It also improved quality of life, as assessed by QOLI (Table 5).
 

Parameter	Mean Value			P value
	Before treatment	After treatment	Mean Change
NTSP	5.9 hrs	7.2 hrs	1.3 hrs	P<0.01
NTA	3.4 times	2.1 times	1.3 times	P<0.01

^{Table 5: Change in QOLI at the end of study as compared to the baseline}

 

Discussion

The efficacy and tolerability of montelukast in seasonal allergic rhinitis has now been well established in placebo controlled trials (Philip et al., 2002). Philip et al. reported a highly significant improvement with montelukast by -0.37 least squares of means, in patients in the 15-81 years age group. It also improved quality of life parameters and was well tolerated.

In another systemic review by Nayak and Ronald (2007), monotherapy of montelukast showed comparable efficacy to loratadine, an antihistaminic. In another meta-analysis (Grainger and Drake-Lee, 2006), a decrease by 3.4% in TNSS has been reported with montelukast monotherapy as compared to placebo and our study is in line with these above mentioned studies. Studies about the efficacy and safety of montelukast as monotherapy in seasonal allergic rhinitis in children aged 2-5 years are rare. Recently, a phase III clinical trial comparing montelukast with a placebo in seasonal allergic rhinitis involving children aged 2-5 years, sponsored by Merck, has concluded. The results of this study are yet to be posted (ClinicalTrials.gov, 2009).

In the present study, the greater proportion of boys (64% vs 36%) is consistent with reported studies (USA Today, 2009). As is evidenced from the results, montelukast is highly effective in decreasing all the symptoms of seasonal allergic rhinitis in children. The effects of montelukast were persistent over the six-week study period. 97% of the children did not require any additional drug for controlling allergic rhinitis symptoms. Montelukast was also well tolerated by children; treatment-induced cough was the most frequently reported adverse effect, closely followed by treatment-induced vomiting, but these adverse effects were not serious in any of the individual patients, and the need to withdraw montelukast from any child never arose.

The effects of montelukast on quality of life were also very impressive and this was reflected in the parents' satisfactory scores. Night-time awakening in children decreased by 38.2%, and the period of night time sleep also increased persistently.

Limitations of the study

The major limitation of the study is the lack of a comparator group, either placebo or active treatment. A comparison with a placebo could not be undertaken due to the denial of permission from the ethical committee, as the research involved children of only 2-5 years of age. The active treatment group comparison was not feasible due to the limited grant available.

Another limitation of the study is the lack of blinding, again due to lack of a comparator group. Moreover, due to ethical considerations, no challenge and de-challenge test was done. Despite these limitations, the present study can to some extent fill the lacunae of lack of studies about montelukast in seasonal allergic rhinitis and can prove to be path-breaker for further studies in this field.

 

Conclusion

From the above discussion, it can be concluded that montelukast could improve the quality of life of children with allergic rhinitis, in addition to being efficacious as monotherapy in seasonal allergic rhinitis in children aged 2-5 years. Moreover it has a considerable safety profile, with persistent results. A study by including an active comparator group is needed to fully establish the results.

 

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Acknowledgements

We are very thankful to Dr Jatinder Sharma (Paediatrician) and Dr Munish Bansal (Otolaryngologist) and acknowledge the help extended by them for recruiting patients and collecting data.

 

List of Tables

Table 1: Change in component-score and TNSS at the end of therapy as compared to baseline

Table 2: Change in component-score and MTTES at the end of therapy as compared to baseline

Table 3: TNSS and MTTES as calculated by least square of means

Table 4: Major reported adverse effects of Montelukast (Quantified)

Table 5: Change in QOLI at the end of study as compared to the baseline

 

Notes

[1] Princy Mittal is a Final Year M.B.B.S. student at Adesh Institute of Medical Sciences & Research, Bathinda-151109 (India) and will be completing her degree of Medical graduation in Dec 2010

Dr. Rajiv Mahajan is an Assistant Professor in the Department of Pharmacology, Adesh Institute of Medical Sciences & Research, Bathinda-151109 (India)

Dr. (Mrs) Kapil Gupta is an Assistant Professor in the Department of Biochemistry, Adesh Institute of Medical Sciences & Research, Bathinda-151109 (India)

 

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To cite this paper please use the following details: Mittal, P., Mahajan, R. and Gupta, K. (2009), 'Efficacy and Tolerability of Oral Montelukast in Seasonal Allergic Rhinitis in Children Aged 2 to 5 Years: An Open Study', Reinvention: a Journal of Undergraduate Research, Volume 2, Issue 2, http://www.warwick.ac.uk/go/reinventionjournal/issues/volume2issue2/mittal Date accessed [insert date]. If you cite this article or use it in any teaching or other related activities please let us know by e-mailing us at Reinventionjournal@warwick.ac.uk