Drug Therapy

Indian Pediatrics 2000;37: 1201-1209.

Montelukast in Childhood Asthma

For more than two decades, no new drug has been introduced for asthma, and we have used the same old drugs in various dosage forms and combinations to give relief to the millions who suffer from this widespread illness. Leukotriene modifiers are an entirely new class of drugs for the treatment of asthma. We now know that asthma is basically a disorder of airway inflammation. The last few years have seen extensive research on mediators of inflamma-tion, including leukotrienes, prostaglandins, neuropeptides, lymphokines, and interleukins. The knowledge gained about these mediators is being put to use to develop new drugs for this old affliction of mankind. Montelukast is one of the results of this scientific search.

Asthma medications are today classified into two groups – the quick relief medications consisting of short acting beta-2 agonists and systemic corticosteroids, and the long term control medications, consisting of long acting beta-2 agonists, inhaled corticosteroids, cromolyn sodium, nedocromil, methylxanthines and the leukotriene modifiers. Patients with mild intermittent asthma (Table I)(1) need only short acting beta-2 agonists; patients with all other classes of asthma need some drug that offers long term control of the disease.

Leukotrienes are chemical mediators of inflammation (Fig. 1). They are formed from arachidonic acid, and are secreted by eosino-phils, mast cells, neutrophils, lymphocytes, macrophages, and basophils(2). Leukotrienes have been found to play a pivotal role in the pathogenesis of asthma(3).The cysteinyl leukotrienes (LTC4, LTD4 and LTE4) play an important part in the generation of the airway inflammation that characterize asthma. They increase vascular permeability, increase edema formation, increase mucus production, and recruit eosinophils and neutrophils(4). The cysteinyl leukotrienes are potent broncho-constrictors, being a thousand times as potent as histamine in this action(5). After allergen challenge, a large increase in production of these cysteinyl leukotrienes is detectable in the bronchoalveolar lavage (BAL) fluid and urine of people with asthma(6). Leukotrienes are responsible for much of the bronchoconstriction during the early asthmatic response; they also mediate part of the bronchoconstriction of the late asthmatic response(7).

   Fig. 1. Pathogenesis of airway obstruction in asthma.

Among the other leukotrienes, leukotriene B4 is also active in the pathogenesis of asthma. It increases airway infiltration of neutrophils and eosinophils, and increases airway reactivity to bronchospastic challenges(2). However, no drug active against this proinflammatory mediator is in clinical use at present.

Drugs that prevent the formation of leukotrienes, as well as those that block their action, are collectively known as leukotriene modifiers. An enzyme, 5-lipoxygenase, is required for the production of the leukotriene; this enzyme requires an activating protein known as FLAP (5-lipoxygenase activating protein). Inhibiting either the enzyme, 5-lipoxygenase, or FLAP, blocks the production of leukotrienes and can curb the airway inflammation of asthma. The only marketed drug for this purpose is zileuton.

The action of the leukotrienes depends on their binding to cellular receptors. Drugs that thwart the asthmatic process by blocking the action of the leukotrienes at their receptors are known as leukotriene antagonists. Three drugs of this class are in use at present – zafirlukast, pranlukast, and montelukast. All three are specifically active against the cysteinyl leuko-trienes by blocking their receptor, CysLT1. Only montelukast has been extensively studied in children.

Montelukast has been extensively studied in people with persistent asthma. It has been found to reduce asthma symptoms, improve airway obstruction (as measured by forced expiratory volume in one second), reduce nocturnal awakenings, and reduce beta agonist require-ment(7-9), signifying better disease control. The drug improves daytime symptoms, and pulmo-nary function, though the improvement seen is less than that with inhaled steroids(10). Montelukast decreases asthma exacerbations and increases asthma control days. The beneficial effects are often evident from the first day of therapy. Montelukast provides benefit even to patients on inhaled corticosteroids(11). Table II shows the actions of this drug.

Many patients with moderate asthma are stable on inhaled steroids but both physician and patient are concerned about the side effects of the drug. Montelukast allows tapering of the dose of inhaled steriod, while continuing the same degree of disease control, in many such patients. In one study(12), 62% of the subjects could reduce their dose of inhaled steroids by 50% or more, with 40% of patients stopping steroids completely. This steroid sparing effect makes montelukast an attractive addition to our therapeutic armamentarium.

Asthma is a heterogenous disease, and the leukotrienes may not be the chief mediator in all patients. Thus we cannot expect montelukast to be effective in all patients. In one study, 34% of patients had no improvement, even after 12 weeks of therapy(10). In the steroid tapering study mentioned above(12), 28% of patients could not reduce their requirement of steroids at all while on montelukast. We do not yet have a way of determining in advance which patients will respond to this drug.

Many patients with mild asthma only have symptoms on exercise, a sign of poor control of the disease. Exercise induced broncho-constriction is an early asthmatic response, which is leukotriene mediated. Montelukast provides protection from bronchoconstriction in these patients(7,13,14). It reduces the fall in FEV1 (forced expiratory volume in one second) after an exercise challenge, and shortens the time to recovery. This effect is seen as long as twenty to twenty four hours after a dose. There is no rebound worsening of lung function after cessation of therapy.

This effect is particularly important in children. Current options for attenuating exercise induced asthma are inhaled beta agonists, cromolyn, or oral theophylline. All of these, with the exception of long acting beta agonists, must be taken shortly before starting the exercise activity, and they provide protection for one to two hours only(15). Montelukast can free the child from the need to plan his activity in advance, as well as from the need to take medication in school.

Three to eight per cent of patients with asthma are hypersensitive to aspirin and other non steroidal anti inflammatory drugs (NSAIDs). Aspirin or an NSAID given to these persons can cause profound, sometime life-threatening, bronchoconstriction. These patients have a several fold increase in leukotriene C4 synthase activity(16), probably due to a gene mutation. The cysteinyl leukotrienes are the leading mediators of the airway reaction that occurs in persons with aspirin-sensitive asthma after exposure to aspirin(16). Leukotriene modifiers are able to prevent this reaction(8) and are the treatment of choice for these patients(7).

Currently, beta agonists have a well defined place in the long term management of asthma. While short acting beta-2 agonists have a role to play in rescue from acute episodes, long acting beta-2 agonists are prescribed for regular use in moderate and severe asthma.

Salmeterol has benefits in the treatment of exercise induced asthma(17). A randomized blinded study comparing it with montelukast found that both drugs provided equal protection at day 3, but montelukast provided greater protection when tested at four and eight weeks after initiation(18). Unlike salmeterol, montelukast does not have a waning of bronchoprotective effect with long term use. Absence of tachyphylaxis gives it a significant advantage over salmeterol.

Orally administered montelukast improved airway function in about one to three hours, compared to five minutes with inhaled salbutamol. The bronchodilator effect is about half that achieved with beta-2 agonists(7). It is thus, not a drug to be used for immediate relief of bronchoconstriction and distress.

Beta-2 agonists improve FEV1 by about 20-30%. The magnitude of benefit with leukotriene antagonists is substantially less, but additive, suggesting that the two types of drugs act on different contractile mechanisms(16).

Inhaled steroids act on several pathways of the inflammatory process, in contrast to the leukotriene antagonists. They are the most effective preventive agents for long term symptom control, improvement in FEV1, and decrease in airway reactivity. They also reduce daytime as well as night time symptom scores, and reduce need for rescue treatment(19). Inhaled steroids have been shown to prevent the airway remodeling and progressive deterioration of lung function that occurs in asthma(2). No such evidence as yet exists for montelukast; being a new drug, its long terms effects are not known at present.

Montelukast achieves lesser improvements than inhaled steroids in FEV1, peak expiratory flow rates, daytime asthma symptoms, nocturnal awakenings, beta-agonist use, and asthma specific quality of life. However, its onset of benefit is quicker, with a greater initial benefit(10). Unlike inhaled steroids, montelukast does not inhibit allergen induced airway hyper-responsive-ness(7). Though it protects the patients against breakthrough asthma attacks, this protection is less than with beclo-methasone(10).

Montelukast acts specifically on the cysteinyl leukotrienes. It is known that neither oral nor inhaled steroids can inhibit the increased synthesis of cysteinyl leukotrienes in response to an allergen exposure(21). This explains the additive effect of montelukast when given with inhaled steroids(11).

Inhaled steroids are currently the best treatment available for long term control of asthma disease. However, they have significant side effects, causing slowing of growth and adrenal suppression(22,23). Growth suppression is seen in children with severe asthma taking high doses of inhaled steroids, and it is possible that the disease itself may be causing the growth suppression. There is still a school of thought that feels that steroid therapy is not justifiable for mild asthma(24). However, not treating these patients appropriately can lead to deterioration of pulmonary function. Montelukast may be the therapy that is acceptable and effective.

Montelukast has been tried mainly for the long term control of chronic forms of asthma. However, a study reported recently(25) used it intravenously and found that it produced a fifteen per cent improvement in FEV1 in fifteen minutes. The authors have suggested that the drug may have a role in the management of acute asthma, which should be investigated. At present, montelukast is not used for acute asthma exacerbations in clinical practice.

Montelukast provides modest improve-ments in FEV1 in children with mild to moderate asthma. It also provides protection against bronchoconstriction in children with exercise induced asthma. There is insufficient data available at present to clearly delineate the place of montelukast in the stepwise approach to asthma therapy. Over the next few years, comparative trials of the drug against cromolyn and corticosteroids will become available, making informed decisions possible. However, some facts are well established already.

• Montelukast will not replace beta-agonists or systemic corticosteroids in the management of acute asthma.

• It is at least as effective as cromolyn in the long term management of asthma.

• It is not as effective as inhaled steroids, but acts as a "steroid sparing" drug in the management of chronic asthma, allowing either reduction in the daily requirement of corticosteroids, or better control of the disease at the same dose of corticosteroids.

• It appears to be a very safe drug in studies till now. Its safety profile is matched only by cromolyn.

• It can probably be used as monotherapy only for mild persistent asthma. For all more severe forms, it will probably be used as add on therapy along with corticosteroids.

• It has a role in moderate asthma with an exercise induced component.

• Montelukast is especially effective in patients with NSAID induced asthma.

Inhaled steroids not only provide symptom control on long term use, but also reduce airway reactivity and inflammation and improve lung function in children with severe and moderate forms of persistent asthma(20). They are, thus, the standard of therapy against which other agents must be compared, though adverse effects are a concern. For children with symptomatic asthma and impairment of normal life, inhaled steroids are the drug of choice. However, for children who have only mild asthma, the adverse effects assume importance, and the leukotriene modifiers will perhaps offer us an alternative.

At present, however, montelukast is seen as a drug which must be taken systemically, with unknown long term effects and side effects. Its effectiveness as monotherapy is not better than other, established, therapeutic agents. As a steroid sparing agent, it needs to be compared scientifically with proven agents like long acting beta agonists, cromolyn, and theo-phylline. Most trials with this drug have been in adults or children older than six years, and it is not recommended for use below this age. Pending the publication of well designed, long term, controlled trials, especially in young children, its place in pediatric asthma thera-peutics is uncertain.

Montelukast has been found to be effective at oral doses of 10 mg per day in adults(9,10, 12,13,18) and 5 mg per day in children(14,26). Higher doses have been tried, but do not give any added benefit. Food does not significantly affect its absorption. Montelukast has a long duration of action, allowing the convenience of a single daily dose. Effective bronchoprotection has been seen 20 to 24 hours after a dose.

Montelukast is made available by the manufacturers as 10 mg tablets and 5 mg chewable tablets for children. This drug is currently recommended only for children above the age of six years. It is usually administered as a single night time dose. The drug is not as yet available in India.

The drug has also been tried intravenously in adults, at a dose of 7 mg(25). Apart from a faster onset of action, there was no significant advantage over the oral route.

One of the chief advantages is that it is an orally administered drug. For many children whose parents refuse to allow inhaled therapy, montelukast may provide a solution that is effective and acceptable.

Another major advantage is that it only needs a single daily dose. Most trials have used the drug as a single evening or night time dose, and have found it to be effective for as long as twenty hours. Compliance with any therapy is known to be inversely proportional to the frequency of dosing, and a single daily dose is probably optimal.

Montelukast achieves perceivable benefit within 24 hours(9). Patient acceptance is always positively influenced by early benefit. Inhaled corticosteroids, for example, take several days to achieve maximal benefit, and patient non-compliance is even a problem. Much depends on the time spent on motivating and educating the patients and parents; a recent study using inhaled fluticasone and budesonide in children aged four to twelve years found that compliance with therapy was almost 100%(19).

There is also a "steroid fear" in the minds of many patients and parents. Physicians also feel that prescribing inhaled steroids may prevent asthma symptoms now, but lead to complica-tions of steroid therapy at a later age(24). A controller drug that replaces steroids in mild asthma and exercise induced asthma is of considerable value.

Montelukast has been found to be a fairly safe drug in the limited time that it has been available. In blinded studies, patient reported side effects were as frequent as with placebo(9,10,13,26). In a comparative study with inhaled salmeterol(18), montelukast was found to have a lesser incidence of adverse events and discontinuations. There is no rebound worsening of asthma after discontinuation of the drug. Though the immediate safety profile appears to be favorable, we do not yet have much data regarding safety on long term use. Extensive use in the future may reveal rare side effects that have not been seen so far.

Zafirlukast, which is another leukotriene receptor antagonist, has been associated with the Churg-Strauss syndrome, a rare, multisystem, allergic granulomatous vasculitis. This has also been reported with montelukast(7,21). The disease may be a coexistent one, being revealed by the reduction of inhaled steroid dose made possible by montelukast.

Asthma is a state of inflammation of the airways, and uncontrolled inflammation leads to progressive damage to the mucosa, collagen deposition, fibrosis, and irreversible damage. This process, known as airway remodeling, eventually begets airway obstruction that cannot be completely reversed.

Leukotrienes are only one of the pathways of airway inflammation. Other mediators such as histamine, prostaglandins, interleukins and platelet activating factor may also have a significant role. Antileukotrienes are potent bronchodilators, and relieve the symptoms of asthma successfully. Palliating the symptoms by using leukotriene antagonists may allow the inflammation to persist, leading to airway remodeling and irreversible obstruction.

Treatment with inhaled corticosteroids has been shown to have widespread effects on inflammatory cells, cytokines and transcription factors. Steroids are anti-inflammatory agents of great efficacy, and act on multiple pathways of airway inflammation. Long term studies have shown inhaled steroids to have beneficial effects on asthma control and lung function(27). No such evidence yet exists for the antileukotrienes. There is widespread concern today about airway remodeling and irreversible airway damage in asthma, and it will be several years before we know whether montelukast is effective in arresting it. Thus, it may be premature to use montelukast as a single therapy for asthma.

Montelukast has been shown to be an effective drug in asthma. It has both anti inflammatory and bronchodilatory effects, and offers protection against both exercise and allergen challenges. Prolonged use is not associated with the tolerance characteristic of salmeterol. It is not as yet available in India, and so nothing can be said about the cost-benefit ratio.

Inhaled corticosteroids are the only intervention to have proven long term benefits in persistent asthma. They thus remain the main-stay of long term asthma treatment. However, the ease of administration of montelukast, coupled with its apparently excellent safety profile, make it an appealing addition to the treatments available for asthma.

Funding: None.
Competing interests: None stated.

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