Mechanisms of Change in Behavioral Cough Suppression Treatment for Refractory Chronic Cough - PROJECT SUMMARY Refractory chronic cough (RCC) is a costly condition that is challenging to treat. While behavioral cough suppression (BCS) therapy has shown efficacy in clinical trials, it is underutilized and the therapeutic mechanisms are unknown. Potential targets for BCS therapy include the ascending and descending neural pathways involved in modulating expression of cough receptors in epithelial tissue, modifying interoception of urge-to-cough (UTC) sensation, and strengthening inhibitory motor networks. Each of these targets would ideally reduce cough frequency and cough sensitivity. Capsaicin, a cough stimulant, desensitizes ascending neural pathways in pain syndromes and chronic rhinitis, showing potential for its use to desensitize cough pathways. Our pilot research on a version of BCS therapy wherein participants with RCC are trained to suppress cough in the presence of repeated nebulized capsaicin (i.e., BSC+CAP), has shown promise in improving cough outcomes. This multi-site randomized clinical trial will evaluate the mechanisms of therapeutic response to BCS therapy and BCS+CAP for RCC. We will recruit 150 participants with RCC, divided into three groups—BCS+Sham, BCS+CAP, and capsaicin stimulation alone (CAP). Participants will attend 12 treatment sessions. Primary outcome measures will be cough sensory threshold (citric acid concentration causing 5 or more coughs; C5), cough suppression ability (difference between citric acid concentration causing 5 or more coughs while trying to suppress cough (CS5) and C5), a measure of cough sensory-motor coupling (difference between first UTC felt and UTC at first dose causing two or more coughs), and cough-related blood oxygen level dependent (BOLD) neural responses with whole-brain fMRI. Secondary measures will include the Leicester Cough Questionnaire (LCQ) and ambulatory cough frequency. It is hypothesized that all treatments will change C5 threshold but only BCS treatments will change UTC sensory-motor threshold difference, cough suppression ability, and central neural networks, suggesting BCS treatments change cough sensory-motor processing, while capsaicin stimulation desensitizes peripheral afferent pathways. It is also hypothesized participants undergoing BCS+CAP will demonstrate the greatest improvement in all measures relative to BCS+Sham and CAP due to a multi-modal treatment benefit (i.e., desensitization, sensory-motor processing, cough inhibition).
