A 2x2 Factorial, Randomized, Open-label Trial to Evaluate Neuromodulators and Cough Control Therapy in Patients With Refractory or Unexplained Chronic Cough

The FORTITUDE trial will provide head-to-head evidence on the benefits and harms of two commonly prescribed neuromodulators (low-dose morphine and pregabalin), the effectiveness of a virtual cough control therapy, exploratory assessment of potential synergy in combining these interventions, and the long-term outcomes of these treatments in patients with refractory or unexplained chronic cough.

Inclusion Criteria: 1. Adults (≥18 years old) with either: 2. Refractory chronic cough (RCC), defined as having one or more identifiable causes of cough (asthma, allergic rhinitis, and/or GERD), but with previous trials of treatment targeting the underlying condition leading to no cough resolution; OR 3. Unexplained chronic cough (UCC), defined as having a cough lasting \>8 weeks with (i) a normal chest X-ray/CT in the last 5 years and since the onset of chronic cough; (ii) FEV1 and FVC ≥80% predicted or \>lower limit of normal (LLN); (iii) FEV1/FVC ≥0.7 or \>LLN; (iv) no evidence of asthma; and (vi) no regular symptoms of nasal/reflux disease. Exclusion Criteria: 1. Those who, in the opinion of the investigator, have previously tried low-dose morphine, pregabalin, and/or CCT with full intervention fidelity for the treatment of RCC/UCC; 2. Are currently taking morphine or pregabalin for the treatment of any indication (i.e., RCC/UCC or chronic pain);\* 3. Are currently taking other centrally-acting medication (i.e., gabapentin, amitriptyline, dextromethorphan) for the treatment of any indication (i.e., RCC/UCC, seizures, or depression);\* 4. Have a history of opioid or substance abuse that, in the opinion of the investigator, may interfere with the conduct of the study; 5. Are a current smoker, or ex-smoker with a \>20 pack-year history who have abstained from smoking for \