Pharmacological regulation of the cough reflex - from experimental models to antitussive effects in man

A wide range of pharmacological agents have been examined in experimentally-induced cough in animal models and healthy human subjects and, to a lesser extent, in patients with chronic cough. Opioids, acting at a putative cough centre in the CNS, and inhaled local anaesthetics, suppressing afferent neural activity, remain the most effective antitussive drugs available in healthy subjects and in patients. Antiasthma drugs like β-agonists, theophylline and glucocorticoids suppress coughing in patients with asthma, but have little direct effect on experimental cough in healthy subjects or in subjects with chronic, dry cough. These data suggest that antiasthma drugs act indirectly by reducing inflammatory mediators in the bronchial mucosa that trigger coughing, rather than directly on any of the physiological components of the cough reflex. The use of cell cultures (e.g. electrophysiologica1 studies of nerve cell excitation), in vitro experiments and animal models are all essential for advancing our understanding of the physiology and pharmacology of respiratory reflexes, even though the ultimate confirmation of pathophysiological mechanisms require carefully conducted clinical experimental studies. Citric acid/capsaicin-induced coughing in conscious guinea-pigs is a most useful model of the cough reflex but it is clear that the antitussive activity of pharmacological agents is most predictive when the drugs are administered systemically. This particular model seems to have a propensity for identifying 'false-positive' drug candidates when they are administered locally to the airways. Further studies are required to refine the model and characterize it relative to pathological coughing in human subjects. There is no doubt that the drugs currently available for suppression of the cough reflex, most of which are sold OTC as part of various self-medication programmes, are inadequate and that there is an unmet medical need, particularly in patients with chronic, non-productive cough. Although opioids possess pronounced antitussive effects also in patients, their side-effect liabilities reduce their utility to a small number of subjects with severe symptoms. Future advancements are dependent on the availability of predictable preclinical and clinical experimental models. The models and mechanisms discussed in this review is a step in this direction, but a deeper understanding of appropriate physiological and pathological processes at the neural and cellular level is necessary for a significant improvement in model development that will, hopefully translate into the identification and clinical development of novel and improved antitussive agents.