Effect of Sublingual Fentanyl on Breathlessness in COPD

The purpose of this study is to test the hypothesis that sublingual fentanyl will improve exercise capacity and dyspnea control in severe COPD patients experiencing persistent breathlessness despite optimal management. To demonstrate the effectiveness of sublingual fentanyl, the investigators suggest a dose of 12,5 mcg. The investigators base this decision on several considerations : * Local practice and experience : the safety of a dose of 12,5 mcg of sublingual fentanyl has been show in the investigators local experience (see section 1.3 Clinical experience with fentanyl). * Although there is not enough information to determine the exact equivalence between sublingual fentanyl and oral morphine, the conversion between intravenous fentanyl and oral morphine can be done. Based on the monograph of fentanyl citrate, 10 mcg of intravenous fentanyl citrate are equivalent to 10 mg of intravenous morphine, which are equivalent to 20 to 30 mg of oral morphine. Subsequently, 12,5 mcg of sublingual fentanyl may be equivalent to a oral morphine dose between 2,5 and 3,75 milligrams. This represent a smaller dose than the dose of 0,1 mg/kg oral morphine that was demonstrated to be safe in a recent study done by a group at McGill in a severe COPD population (Abdallah et al. Eur Respir J 2017; 50: 1701235). * The study will only include patients who are already on morphine, because they represent the target population and have less risk of adverse events than an opioid-naive population. * To ensure safety, participants will be actively monitored during the study. A doctor will be present at administration of the drug and the antidote, naloxone, will be readily available if needed. Participants will be monitored on-site for 30 minutes after completion of CPET and discharge only if no evidence of side effects. Participants will be informed to not drive for 24 hours following each period of treatment. A phone call follow-up will be done 24-48 hours after treatment visits. General Objective: The general objective is to demonstrate the role of sublingual fentanyl liquid to improve exertional shortness of breath in patients with severe to very severe COPD. Primary Objective : The primary objective is to evaluate in severe/very-severe COPD the effect of 12,5 mcg fentanyl sublingual liquid as compared with placebo, on i) post-dose difference in exertional breathlessness at isotime (Isotime definition : highest equivalent 2 min interval of exercise completed by a given participant) ii) Post-dose difference in exercise endurance time (EET) The study is a multicentred randomized clinical trial, triple-blinded, cross-over design, comparing fentanyl sublingual at a dose 12,5 mcg to placebo in severe/very-severe COPD already taking low dose of morphine because of refractory dyspnea. To detect a minimally clinically important (MCID) difference of 1 Borg unit (40) at iso-time between treatments, we assume an α of 0.05 and a within-subject standard deviation of 1 Borg unit: a total of 20 patients will provide \>80% power; assuming an attrition rate of 20%, a total of 24 patients will be recruited for this study. All data will be de-nominalized in order to respect privacy. Data will be collected in an anonymous data sheet, protected by a password. Only investigators and statistician will have access to this data sheet. The principal analysis of the relative change in dyspnea intensity at iso-time (primary end-point) after treatment with morphine sulfate vs. placebo will be conducted using an unadjusted paired t-test. Secondary analyses to assess treatment responses on secondary end-points (e.g. arterialized capillary PCO2, EET, dyspnea unpleasantness, ventilation, breathing pattern, operating lung volumes, etc.) will be done using paired t-tests adjusted (Bonferroni) for multiple comparisons. Pearson correlations will be used to establish associations between intra-subject post-dose differences in iso-time dyspnea intensity ratings and relevant independent variables (e.g. arterialized capillary PCO2, ventilation, breathing pattern, MDP results, etc.) and various baseline patient characteristics (possible covariates). Stepwise multiple regression analysis will then be carried out with significant independent variables and relevant covariates.