Low-dose morphine and airway sensations in refractory chronic cough: a randomised control trial.

Background: Low-dose morphine is recommended as an antitussive agent for refractory chronic cough (RCC), although its precise mechanism of action remains unknown. We hypothesised that noxious airway sensations ( Methods: 22 RCC patients (median age 65 years; 83% female) reporting a clinical response to low-dose morphine withdrew from therapy and enrolled in a double-blinded, randomised, placebo-controlled, crossover trial comparing the effects of their usual dose of morphine with those of a matched placebo. The sensations evoked by citric acid inhalation were assessed at baseline and at the end of each 5-7-day treatment period. The efficacy of morphine, compared with placebo, was assessed by objective cough monitoring and patient-reported outcomes at the same time points. Findings: Compared with placebo, low-dose morphine improved the rating of all sensations provoked by citric acid inhalation (all p<0.05), but the cough threshold (C2) was not changed (p=0.61). 24-hour cough frequency was reduced by 71.8% with low-dose morphine, compared with placebo treatment (p<0.001), and all patient-reported outcomes significantly improved. Interpretation: This trial suggests that the antitussive action of low-dose morphine may be a consequence of modulation of noxious airway sensations and provides the first objective evidence of its efficacy in RCC patients reporting a clinical response.