Excessive airway narrowing is an important determinant of fatal asthma. This pathophysiological feature is characterized by the absence of a dose-response plateau to methacholine (Mtc). We investigated if the leukotriene receptor antagonist (LTRA) montelukast (Mont) can induce a dose-response plateau to Mtc in adult asthmatic patients not on controller therapy, and, hence, protects against excessive airway narrowing. Thirty-one asthmatic patients (13 male patients, 18-50 years old; forced expiratory volume in 1 second [FEV(1)], >70% predicted; PD(20), <3.9 micromol of Mtc) on short-acting beta 2-agonists p.r.n. only with a twice-documented absence of dose-response plateau, participated in a double-blind, parallel study with Mont (10 mg) or placebo once daily for 12 weeks. Mtc dose-response curves (0.03-256 mumol or >40% FEV(1) decline) were repeated every 4 weeks. The primary objective was induction of a plateau response (defined as >/=2 FEV(1) values within a 5% range), and, secondarily, changes in PD(20) and maximal decline in FEV(1) after 12 weeks. Mean baseline FEV(1), FEV(1)/forced vital capacity, PD(20), and maximal decline in FEV(1) were 91% pred, 78%, 0.46 micromol, and 48.9%, respectively, with no differences between the groups. After 12 weeks, a dose-response plateau was observed in two patients (Mont) and one patient (placebo) (NS), and comparison of changes from baseline in maximal decline in FEV(1) or PD(20) revealed no significant differences between groups. Twelve weeks of treatment with Mont neither induced a plateau response nor affected maximum FEV(1) response or PD(20). Our findings, therefore, suggest that monotherapy with a LTRA does not protect against excessive airway narrowing in adult asthmatic patients not on inhaled corticosteroids.