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

Background Low dose morphine is recommended as an anti-tussive 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 Twenty-two RCC patients (median age 65 years; 83% female) reporting a clinical response to low dose morphine, withdrew the therapy and enrolled into a double-blinded, randomised, placebo-controlled, crossover study comparing the effects of their usual dose of morphine to 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 (PROs) 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). Twenty-four hour cough frequency was reduced by 71.8% over placebo treatment (p<0.001) and all patient reported outcomes significantly improved. Interpretation This study suggests 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.