Question addressed by the study: Endogenous opioids (endorphins) have been reported to modulate exercise-induced breathlessness, but the relative contribution of peripheral opioid receptors has not been tested. Materials, participants and methods: This was a double-blind, randomised, three-arm, cross-over trial in outpatients with spirometry-verified moderate to severe chronic obstructive pulmonary disease. Participants undertook an incremental symptom-limited treadmill test followed by five endurance treadmill tests at 75% of their maximal work rate; two tests for familiarisation and three tests 30 min after intravenous injection of either methylnaltrexone 0.3 mg��kg���1 (blocking peripheral opioid receptors only) or naloxone 0.1 mg��kg���1 (blocking both central and peripheral opioid receptors) or normal saline, in randomised order. The primary end-point was the regression slope between breathlessness intensity (0���10 numerical rating scale) and oxygen consumption (V���O2) during the walk tests, comparing methylnaltrexone and placebo using a paired t-test. Results: 17 participants completed the trial: median (range) 66 (55���82) years; 15 males; mean��SD forced expiratory volume (FEV1) 53.8��17.6% predicted; FEV1/forced vital capacity ratio 0.55��15.9. There was no statistically or clinically significant difference in the primary end-point (regression slope of breathlessness intensity and V���O2) for methylnaltrexone (p=0.498) or naloxone (p=0.804), compared to placebo. Secondary outcomes were similar between the three treatment groups, including peak and mean breathlessness intensity and unpleasantness, exercise capacity, endurance time and leg fatigue. Answer to the question: Blocking peripheral opioid receptors (methylnaltrexone) or peripheral and central opioid receptors (naloxone) did not appear to modulate breathlessness intensity nor exercise capacity when compared with placebo (no blockade).