Patients with chronic obstructive pulmonary disease (COPD) commonly suffer from breathlessness, deconditioning, and reduced health-related quality of life (HRQL) despite best medical management. Opioids may relieve breathlessness at rest and on exertion in COPD.We aimed to estimate the efficacy and safety of opioids on refractory breathlessness, exercise capacity, and HRQL in COPD.This was a systematic review and metaanalysis using Cochrane methodology. We searched Cochrane Central Register of Controlled Trials, MEDLINE, and Embase up to 8 September, 2014 for randomized, double-blind, placebo-controlled trials of any opioid for breathlessness, exercise capacity, or HRQL that included at least one participant with COPD. Effects were analyzed as standardized mean differences (SMDs) with 95% confidence intervals (CIs) using random effect models.A total of 16 studies (15 crossover trials and 1 parallel-group study, 271 participants, 95% with severe COPD) were included. There were no serious adverse effects. Breathlessness was reduced by opioids overall: SMD, -0.35 (95% CI, -0.53 to -0.17; I(2), 48.9%), by systemic opioids (eight studies, 118 participants): SMD, -0.34 (95% CI, -0.58 to -0.10; I(2), 0%), and less consistently by nebulized opioids (four studies, 82 participants): SMD, -0.39 (95% CI, -0.71 to -0.07; I(2), 78.9%). The quality of evidence was moderate for systemic opioids and low for nebulized opioids on breathlessness. Opioids did not affect exercise capacity (13 studies, 149 participants): SMD, 0.06 (95% CI, -0.15 to 0.28; I(2), 70.7%). HRQL could not be analyzed. Findings were robust in sensitivity analyses. Risk of study bias was low or unclear.Opioids improved breathlessness but not exercise capacity in severe COPD.