Effectiveness and safety of opioids on breathlessness and exercise endurance in patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis of randomised controlled trials

Background: Opioids are recommended to treat advanced refractory dyspnoea despite optimal therapy by the American Thoracic Society clinical practice guidelines, while newly published randomised controlled trials of opioids in chronic obstructive pulmonary disease yield conflicting results. Aim: This study aimed to evaluate the effectiveness and safety of opioids for patients with chronic obstructive pulmonary disease. Design: Systematic review and meta-analysis (PROSPERO CRD42021272556). Data sources: Databases of PubMed, EMBASE and CENTRAL were searched from inception to 2022 for eligible randomised controlled trials. Results: Twenty-four studies including 975 patients, were included. In cross-over studies, opioids improved breathlessness (standardised mean difference, -0.43; 95% CI, -0.55 to -0.30; I-2 = 18%) and exercise endurance (standardised mean difference, 0.22; 95% CI, 0.02-0.41; I-2 = 70%). However, opioids failed to improve dyspnoea (standardised mean difference, -0.02; 95% CI, -0.22 to 0.19; I-2 = 39%) and exercise endurance (standardised mean difference, 0.00; 95% CI, -0.27 to 0.27; I-2 = 0%) in parallel control studies that administered sustained-release opioids for more than 1 week. The opioids used in most crossover studies were short-acting and rarely associated with serious adverse effects. Only minor side effects such as dizziness, nausea, constipation and vomiting were identified for short-acting opioids. Conclusions: Sustained-release opioids did not improve dyspnoea and exercise endurance. Short-acting opioids appeared to be safe, have potential to lessen dyspnoea and improve exercise endurance, supporting benefit in managing episodes of breathlessness and providing prophylactic treatment for exertional dyspnoea.