Breathing discomfort (dyspnea) and activity limitation are dominant symptoms of chronic obstructive pulmonary disease (COPD) and contribute to poor health-related quality of life in this population. Several small, uncontrolled studies and published case reports have provided evidence that inhaled fentanyl, a powerful pain relieving (opioid) medication, may be used to effectively reduce breathing discomfort in patients with advanced disease. However, the mechanisms of this improvement remain unclear. Therefore, the investigators plan to conduct the first randomized, double-blind, placebo-controlled, crossover study designed to explore the possible mechanisms of action of inhaled fentanyl on activity-related dyspnea and exercise performance in patients with advanced COPD.

Inclusion Criteria:

• Post-bronchodilator forced expiratory volume in 1 sec (FEV1) 30-79% predicted, FEV1/forced vital capacity (FVC) ratio <70%;
• Clinically stable as defined by no changes in medication dosage or frequency of administration with no exacerbations or hospital admissions in the preceding 6 weeks;
• A cigarette smoking history ≥20 pack-years;
• Significant chronic activity-related dyspnea as defined by a Baseline Dyspnea Index focal score ≤ 6;
• Body mass index (BMI) between 18.5 and 30.0 kg/m2;
• Able to perform all study procedures and provide/sign informed consent.

Exclusion Criteria:

• A diffusing capacity of the lung for carbon monoxide (DLCO) <40 %predicted;
• Presence of active cardiopulmonary disease other than COPD that could contribute to dyspnea and exercise limitation;
• Clinical diagnosis of sleep disordered breathing;
• A history/clinical evidence of asthma, atopy and/or nasal polyps;
• History of allergy or adverse reaction to fentanyl;
• Presence of important contraindications to clinical exercise testing, including inability to exercise because of neuromuscular or musculoskeletal disease(s);
• Use of daytime oxygen or exercise-induced arterial oxygen desaturation to <80% on room air;
• Use of antidepressant drugs (i.e., monoamine oxidase inhibitors, serotonin reuptake inhibitors) in previous 2 weeks;
• Use of opioid or pain relieving drugs (e.g., morphine, fentanyl, oxycodone, hydromorphone, methadone, levorphanol, codeine, hydrocodone, meperidine) in previous 4 weeks.

During visit, with appropriate follow-up to resolution of adverse event