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 (e.g. throat irritation, tickle, urge to cough) described by RCC patients play a role in initiating coughing and are lessened by morphine. 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.