Effect of l-menthol on breathlessness and exercise endurance in COPD: a randomised crossover trial

Breathlessness is a leading cause of disability and reduced quality of life in 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.

This was a double-blinded, randomised (ratio 1:1), crossover trial (RCT) of l-menthol inhalation versus placebo. 20 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 randomised 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).

Compared with placebo, inhaled l-menthol reduced breathlessness intensity at isotime (mean difference -0.8, 95% CI -1.6-0.0; p=0.042), corresponding to a moderate effect size (Cohen's d= -0.49). Isotime breathlessness unpleasantness (-0.7, -1.7-0.3) and emotional response score was lower with L-menthol (-2.2, -4.4-0.0). Leg discomfort (-0.5, -1.3-0.2) was numerically lower, EET was longer (0.9 min, -0.7-2.5) and physiological responses were unchanged.

Inhalation of l-menthol reduced the intensity and emotional response of exertional breathlessness and increased the EET compared with placebo in patients with COPD. The unchanged physiological responses support a central brain effect and l-menthol might be a promising new treatment.