Endogenous opioids are released during exercise and have been demonstrated to induce mast cell degranulation when they are administered intradermally. Thus, these peptides may play a role in the pathogenesis of exercise-induced bronchospasm (EIB). However, in two previous studies, intravenous naloxone did not provide significant protection from EIB. To determine if these failures were due to inadequate dosage (pharmacokinetic failure) or lack of an inherent pharmacologic effect (pharmacodynamic failure), the present study was conducted with nalmefene (Key Pharmaceuticals, Inc., Miami, Fla.), a slowly metabolized, orally bioavailable opiate antagonist, with 30 times the potency of naloxone. Ten subjects with mild intermittent asthma and a greater than or equal to 20% decrease in FEV1 after a standardized exercise test were studied. nalmefene, 20 mg, and identically appearing placebo tablets were administered orally in a double-blind, randomized, crossover design 2 hours before bronchoprovocation. Treadmill exercise was performed for 6 minutes at a minute ventilation of 55% to 66% of the calculated maximum voluntary ventilation and not exceeding 75% to 85% maximal heart rate for age. Spirometry was performed before and 3, 5, 8, 10, and 15 minutes after exercise. The mean decrease in FEV1 after exercise was 28.6 +/- 4.5% with placebo and 30.3 +/- 4.5% with Nalmefene (p = 0.6; beta = 0.04 for a 15% difference). Thus, we conclude that narcotic antagonists do not alter airway reactivity to exercise. In addition, these data suggest that endogenous opioids probably do not play an important role in the pathogenesis of EIB.