Effect of L-menthol on breathlessness and exercise endurance in COPD: a randomized crossover trial

Background and objective Breathlessness is a leading cause of disability and reduced quality of life in chronic obstructive pulmonary disease (COPD). Inhaled L-menthol may reduce breathlessness but data on its effect on exertional breathlessness is limited. We aimed to evaluate the effect of inhaled L-menthol on exertional breathlessness and exercise capacity in patients with COPD. Methods This was a double-blinded, randomized (ratio 1:1), crossover trial (RCT) of L-menthol inhalation versus placebo. Twenty participants with COPD performed two constant-load cycle cardiopulmonary exercise tests (CPET) to exhaustion, with either L-menthol or placebo (strawberry) scented patch in the mask in randomized order. The primary outcome was the difference in breathlessness intensity (Borg 0–10 scale) at isotime. Secondary outcomes were change in breathlessness unpleasantness and leg-fatigue at isotime, exercise endurance time (EET), exertional physiological responses, and multidimensional breathlessness (MDP). Results Compared with placebo, inhaled L-menthol reduced breathlessness intensity at isotime, mean difference −0.8 ([95% confidence interval] −1.6, 0.0; p=0.042), corresponding to a moderate effect size (Cohen's d=−0.49). Iso-time breathlessness unpleasantness (−0.7; −1.7, 0.3) and emotional response score was lower with L-menthol (−2.2; −4.4 to 0.0). Leg discomfort (−0.5; −1.3, 0.2) were numerically lower, exercise endurance time (EET) was longer (0.9 min; −0.7, 2.5) and physiological responses were unchanged. Conclusion Inhalation of L-menthol reduced the intensity and emotional response of exertional breathlessness and increased the EET compared to placebo in patients with COPD. The unchanged physiological responses support a central brain effect, and L-menthol might be a promising new treatment.