Effect of Sublingual Fentanyl on Breathlessness in COPD

Inclusion Criteria: * Male or female aged ≥ 40 years * Cigarette smoking history ≥10 pack years * Clinical diagnosis of severe to very severe COPD, i.e. post-β2-agonist FEV1 \<50% and FEV1/FVC \<0.70 * Chronic activity-related dyspnea, define as any one or combination of a modified MRC of 3-4 or a BDI focal score ≤ 8 * Uncontrolled daily activity-related dyspnea despite optimal medical treatment, including oral morphine treatment at a dose of a least 4 mg per day * No change in medication dosage or frequency of administration in the previous 2 weeks * No exacerbations or hospitalizations in the preceding 4 weeks Exclusion Criteria: * CO2 retention, defined as a resting arterial/capillary PCO2 of \>50 mmHg * Self-reported history of addiction/substance abuse * Acute alcoholism * Presence of important contraindications to cardiopulmonary exercise testing (CPET) * History of hypersensitivity to fentanyl or any component of the formulation * Actual use of methadone * Concurrent use or use within 14 days of a monoamine oxidase (MAO) inhibitor * Severe CNS depression * Convulsive disorders * Known or suspected mechanical GI obstruction (e.g., bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (e.g., ileus of any type) * Increased cerebrospinal or intracranial pressure and head injury * Active mouth mucositis * Dementia diagnosis or significant neurocognitive problems * History of severe chronic kidney disease (stage 4-5) * Women of child bearin…