Extended-Release Morphine for Chronic Breathlessness in Pulmonary Arterial Hypertension—A Randomized, Double-Blind, Placebo-Controlled, Crossover Study

Research output: Contribution to journalArticle


Context: Pulmonary arterial hypertension (PAH) affects people of all ages and is associated with poor prognosis. Chronic breathlessness affects almost all people with PAH. Objectives: This randomized, placebo-controlled, double-blind, crossover study aimed to evaluate the effects of regular, low-dose, extended-release (ER) morphine for PAH-associated chronic breathlessness. Methods: Participants with PAH-associated chronic breathlessness were randomized to 1) seven days of ER morphine 20 mg, 2) seven-day washout, and 3) seven days of identically looking placebo, or vice versa. Primary end points were breathlessness “right now”—morning and evening—measured with a Visual Analogue Scale. Secondary end points included additional breathlessness measures, quality of life, function, harms, and blinded treatment preference (ACTRN12609000209291). Results: Within a period of seven years, 50 patients were assessed in detail and 23 (46%) were randomized (despite broad eligibility criteria). Four participants withdrew while taking morphine. Nineteen participants completed the study. Breathlessness “right now” was higher on morphine compared with placebo both for morning [mean (M) ± SD 31.7 ± 25 mm vs. 26.9 ± 22 mm; effect size (80% CI) = −0.22 (−0.6 to 0.2)] and evening [(M ± SD 33.5 ± 28 mm vs. 25.6 ± 21 mm; effect size (80% CI) = −0.33 (−0.8 to 0.1)]. All secondary measures of breathlessness were higher with morphine as were nausea and constipation. Conclusion: This study does not support a Phase III study of ER morphine for people with PAH-associated chronic breathlessness. Recruiting to the target sample size was difficult, the direction of effect in every measure of breathlessness favored placebo and morphine generated more harms.


  • Diana H. Ferreira
  • Magnus Ekström
  • Dimitar Sajkov
  • Zac Vandersman
  • Danny J. Eckert
  • David C. Currow
External organisations
  • Flinders University
  • Flinders Medical Centre
  • University of Technology Sydney
  • University of New South Wales
  • University of Hull
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Respiratory Medicine and Allergy


  • Chronic breathlessness, effectiveness study, morphine, pulmonary arterial hypertension, randomized controlled trial
Original languageEnglish
Pages (from-to)483-492
Number of pages10
JournalJournal of Pain and Symptom Management
Issue number4
Publication statusPublished - 2018
Publication categoryResearch