Allergic rhinitis (AR) is now being acknowledged as a global health burden with estimates highlighting that 10%–25% of the population worldwide is affected by the disease. (1,2) It is regarded to be an inflammatory condition of the upper respiratory tract and is coupled with one or more classical symptoms of sneezing, itching, nasal congestion, and rhinorrhea. (3)
Asthma is a heterogeneous disease encompassing a variety of respiratory symptoms like cough, shortness of breath, wheezing, or chest tightness, and the presence of a variable expiratory airflow limitation. (4) Studies showed that rhinitis is a significant risk factor for developing asthma both in adults and children. (5)
Research documents Allergic rhinitis to be affecting 10% and 30% of all adults and 40% of children globally (6), depending on the population studied. According to a survey of the Indian population, as high as 20–30% of Indians suffer from allergic rhinitis; whereas symptoms of rhinitis were reported in 75% of children and 80% of asthmatic adults. (7)
Usually regarded to be IgE-mediated hypersensitivity to aeroallergens, allergic rhinitis has been categorized into 2 types; seasonal and perennial. Aggravating due to a complex allergen-driven mucosal inflammation owing to an interplay between resident and infiltrating inflammatory cells, allergic rhinitis if not controlled at the earliest can lead to severe long term complications like chronic sinusitis, aggravation of nasal polyps, permanent hearing impairment (as a result of chronic otitis), sleep apnea and complications thereof, craniofacial abnormalities, decreased long-term productivity and increased propensity to develop asthma. (8)
Effective Treatment of allergic rhinitis is aimed to achieve quick and optimal symptom control, not only over the entire day but also at night (9). Due to its high prevalence rates and the tendency of causing significant medical impact if poorly controlled, timely management of AR remains a challenge to physicians. This article re-evaluates the role of the two most widely used drug combinations – Montelukast (a leukotriene receptor antagonist) and levocetirizine (a second-generation antihistamine) in controlling allergic rhinitis successfully.
Allergic rhinitis and asthma – how are they linked?
Both AR and asthma are IgE-mediated allergies, triggered by similar allergens and have inter-related inflammatory and pathophysiological mechanisms. Therefore, the presence of AR is considered a risk factor for, both the incidence as well as the severity of, asthma. (10)
The CARAS Survey documented the high prevalence of concomitant AR with asthma in Indian patients. The survey further noted the positive link between perennial AR and severity of asthma, suggesting that patients with perennial AR may be at a higher risk of developing more severe asthma. The high use of oral steroids indicates that the presence of concomitant AR in asthmatics may be associated with worsening asthma symptoms. (10)
The international treatment guidelines, including Allergic Rhinitis and its Impact on Asthma (ARIA) currently recommend that clinicians check for the presence of asthma in patients with allergic rhinitis, and vice versa, so that an integrated therapeutic approach for the 2 diseases can be appropriately applied. (11)
Role of Montelukast and Levocetirizine in allergic rhinitis and asthma-
Pharmacological Effects of Levocetirizine: Antihistamines are effective in reducing pruritis, sneezing, and watery rhinorrhea. Second-generation antihistamines have become increasingly popular because of their comparative efficacy and lower incidence of adverse effects relative to their first-generation counterparts. (12)
Levocetirizine, a potent second-generation antihistamine is approved for the relief of early phase symptoms of seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR) in adults and children aged more than 6 years. (13)
Montelukast: Mechanism of Action (MOA)- Montelukast binds with high affinity to the cysteinyl leukotriene receptor for leukotrienes D4 and E4 that are involved in the inflammatory process that may cause asthma and allergic rhinitis signs and symptoms. When bound to leukotriene receptors, montelukast inhibits leukotriene physiologic effects (such as airway edema, smooth muscle contraction, and impairment of normal cellular activity) without exhibiting any agonist activity. (14) Montelukast also effectively inhibits cysteinyl leukotriene receptors and reduces daytime and nighttime nasal (i.e. late-phase) symptoms of patients with rhinitis (9).
Ample evidence now affirms that the combination therapy of montelukast with antihistamine provides enhancing and complementary effects, (15) thereby reducing the symptoms more effectively. Supporting studies point out that concomitant levocetirizine and montelukast treatment are better as compared to monotherapy with levocetirizine on quick control of symptoms and quality of life in AR (9).
How effective is the combination vs monotherapy or other combinations-quoting studies
Early studies had confirmed that concomitant therapy of levocetirizine with montelukast showed statistically significant improvement in nasal symptoms as compared to monotherapy (15,16).Evaluating the effect of combination therapy of montelukast and levocetirizine on the Indian population, researchers concluded that the overall daytime nasal symptoms score was superior with the combined therapy as compared to monotherapy with either drug. The team further elaborated that secondary endpoints and global impression results are also supporting the therapeutic benefit of fixed-dose combination over monotherapy. (17)A unique comparative study analyzing the cost-effectiveness of montelukast-levocetirizine vs montelukast-fexofenadine in patients of allergic rhinitis noted that the cost of the montelukast-levocetirizine group was Rs. 6.6 per day whereas it was Rs. 10.07 per day in the montelukast-fexofenadine group, thus concluding montelukast-levocetirizine combination was cost-effective as compared to the montelukast-fexofenadine for the treatment of AR. This study has special implications in developing countries like India patients where patients have less affordability for costly medicines. (18)Yet another study by Ciebiada M et al., found that the combination of antihistamine and montelukast produced a substantially greater improvement, especially for congestion score, in comparison with antihistamine and montelukast administered separately (19). They also reported that a combination of montelukast levocetirizine is more effective than monotherapy for persistent allergic rhinitis.A study by Mi-Kyeong Kim et al, investigating the efficacy and safety of a fixed-dose combination of montelukast and levocetirizine in patients with perennial allergic rhinitis with mild to moderate asthma concluded that the combination was more effective than monotherapy and also demonstrated a safe and well-tolerated profile. (20)A study by Vipan Gupta et al., reported that montelukast, a leukotriene receptor antagonist with levocetirizine is effective and safe in Indian patients of allergic rhinitis and may be of more clinical utility in the alleviation of residual symptoms and improvement of quality of life associated with allergic rhinitis. (15)
Current guidelines- The multi-disciplinary expert panel from the International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR: AR) documents that combination therapy is an effective therapy in patients whose symptoms are incompletely controlled with oral antihistamine monotherapy, with particular emphasis on a subset of patients with concurrent asthma. (10)
Allergic Rhinitis, if left untreated can quickly culminate into severe complications. Further, estimates reveal that 80% of patients with asthma have allergic rhinitis. Under such scenarios rapid and optimal drug therapy is regarded to be the mainstay of successful management.
The therapeutic effectiveness of treating nasal symptoms is enhanced by a combination of levocetirizine and montelukast, by combatting both early- and late-phase reactions in allergic rhinitis. This drug combination has a time-tested efficacy profile and has proven its superiority in managing the early and late phase symptoms of AR.
Acknowledging the extensively documented efficacy of the montelukast-levocetirizine combination therapy in allergic rhinitis, physicians should be aware of the pros and cons of this combination. Standing the test of time successfully, this combination therapy can go a long way in alleviating the symptoms of allergic rhinitis and associated co-morbidities in an unprecedented way.
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