Leukotriene Modifier Therapy of Rhinitis and Nasal Polyps

Leukotriene Modifier Therapy of Rhinitis and Nasal Polyps By John Murray

"LEUKOTRIENE MODIFIER THERAPY OF RHINITIS AND NASAL POLYPS"
John Murray, MD, PhD
otohns.net International Advisory Board
Departments of Medicine and Pharmacology

Leukotrienes are a group of related compounds released from mast cells and eosinophils during an allergic reaction. These mediators were originally described in the 1930's as slow reacting substance of anaphylaxis (SRS-A). Among these, leukotriene D4 is now recognized to probably play the most important role in allergic reactions. The importance of the discovery of leukotrienes and their role in allergic responses has been recognized by the award of two Nobel Prizes over the last 20 years. During the past decade, a tremendous effort has been invested in the development of a class of drugs designed to modify the effects of leukotrienes.

The most convincing evidence for the role of leukotirnes in the pathogenesis of allergic reactions has been in asthma. Leukotrienes have been shown to contribute to both the clinical and pathologic consequences of this disease in some asthmatics, although predetermining which ones has not been defined and requires empirically accessing the clinical response after a trial of medication. Drugs designed to alter the effects of leukotrienes in the asthmatic airway have been developed as the first new class of asthma therapies in the past 25 years, and recently received approval for use in asthma. The modulation of the effects of leukotrienes has been approached in two ways thus far: directly inhibiting the enzyme that produces the leukotrienes and antagonizing the action of the leukotriene at the level of the receptor. Zyflo (zileuton) is only inhibitor of the enzyme available, while Singulair (montelukast) and Accolate (zafirulast) are available as leukotriene receptor antagonists.

In addition to their proven efficacy in asthma, other conditions including allergic rhinitis, irritable bowel, psoriasis and rheumatoid arthritis have been examined for possible therapeutic effects. Based on the studies performed to date, there is some suggestion that there may be a beneficial role for these drugs in the treatment of rhinitis, but not in these other conditions. The evidence to substantiate a clinical benefit in rhinitis is still evolving. Initial results from studies performed in asthmatics have reported a mild but significant reduction in nasal congestion only. An initial report indicates an additive, beneficial effect with Singulair and Claritin in combination not only in asthmatic but also rhinitis symptoms. Only one comparison trial in a small number of patients has examined nasal steroids to a leukotriene modifier and found that the nasal steroid was superior to Accolate.

A primary focus for possible therapy for leukotriene modifiers in the upper airway is their use patients with polyps, and in particular those demonstrating aspirin sensitivity. Aspirin blocks the cyclooxygenase enzyme that produces prostaglandins from arachidonic acid. Through some yet fully understood mechanism, leukotriene production that is also derived from arachidonic acid is increased by the inhibition of the cyclooxygenase with aspirin or other non-steroidal anti-inflammatory drugs. Large increases in leukotriene production can be documented in these individuals when challenged with aspirin. Several clinical trials have shown efficacy of leukotriene modifiers in abrogating the acute drop in lung function with aspirin challenge. As many of these aspirin sensitive asthmatics have nasal polyps and these polyps can produce leukotrienes, there have been antidotal reports using these drugs to treat the nasal polyposis. Thus far, however, there has only been one report published of a patient with nasal polyps improving clinically from refractory congestion related to the polyps over a several month treatment period with Accolate. An additional brief report examined the use of Zyflo in an unblinded fashion to treat several aspirin sensitive asthmatics with anosmia. The sense of smell was reported to improve after institution of treatment in these patients.

In summary, although efficacious in the treatment of asthma in certain patients, demonstration of significant clinic efficacy on rhinitis parameters other than congestion has not been conclusive thus far. This may result from the fact that in most individuals, leukotrienes may not be a significant mediator of their upper airway disease as they are in the lower airway. In contrast, histamine appears to play a greater role in the manifestations of the symptoms of upper airway disease, and less so in the lungs. Additional studies to document efficacy of leukotriene modifiers in nasal polyposis, particularly in those who are aspirin sensitive, are currently under consideration.

Until there is further evidence for efficacy of these drugs, it would be prudent to continue the standard of therapy for rhinitis and polyposis. This would include the use of nasal and/or oral steroids as well as antihistamines and decongestants. If the disease remains refractory or side effects preclude the use of these medications, a trial of a leukotriene modifier could be considered. Based on the results from the asthma studies, a long term trial is necessary to access whether these drugs would be efficacious in any one individual. Therefore, a patient should be treated for at least several weeks to a month before deciding about the clinical response to the medication. It is unclear whether using a drug such as an inhibitor of leukotriene production (Zyflo) is any more beneficial than using a receptor antagonist (Singulair or Accolate). Studies in asthma do not appear to favor one approach or drug over the other, and there are no data as yet to consider anything differently in the upper airway.

If a therapeutic trial is indicated, the easiest drug to administer with the least side effects and drug interactions would point towards Singulair. This is dosed once a day at 10 mg (5 mg between the ages of 6 and 14). Zyflo is dosed four times a day at 600 mg and Accolate is given twice a day at 20 mg without food. In general these drugs are well tolerated and in particular do not appear to predispose individuals to infection that was a concern due to the fact that leukotrienes are involved in the recruitment of inflammatory cells. The cost for any of these treatments is more than other available therapies including nasal steroids and second generation antihistamines. Furthermore, not all pharmacy plans currently carry these, and it may be difficult to get approval for this non-indicated condition. The future devolvement of other drugs in this class or studies demonstrating an effect in patients specifically identified as responsive to this therapy may provide an additional effective therapeutic option for medical therapy of upper airway diseases.