Mechanisms and Rationale for Targeted Therapies in Refractory and Unexplained Chronic Cough

Abstract

Chronic cough, defined as a cough lasting > 8 weeks, is a common medical condition that exerts a substantial physical, mental, and social burden on patients. A subset of patients with chronic cough are troubled with a cough that persists despite optimal treatment of presumed associated common and uncommon conditions (refractory chronic cough; RCC) or in which no diagnosable cause for cough can be identified despite extensive assessment (unexplained chronic cough; UCC). Many of these patients exhibit clinical features of cough hypersensitivity, including laryngeal paresthesia, hypertussia, and allotussia. Over-the-counter cough remedies are ineffective and can lead to intolerable side effects when used for RCC/UCC, and the lack of approved treatments indicated for these conditions reflects a major unmet need. An increased understanding of the anatomy and neurophysiology of protective and pathologic cough has fostered a robust clinical development pipeline of several targeted therapies for RCC/UCC. This manuscript reviews the mechanisms presumed to underly RCC/UCC together with the rationale and clinical evidence for several targeted therapies currently under clinical investigation, including transient receptor potential channel antagonists, P2X3-receptor antagonists, voltage-gated sodium channel blockers, neuromodulators, and neurokinin-1-receptor antagonists. Finally, we provide an overview of targets that have been investigated in preclinical models of cough and other airway diseases that may hold future promise for clinical studies in RCC/UCC. Development of targeted therapies with different sites of action may foster a precision medicine approach to treat this heterogeneous, underserved patient population.

Figure 1

The anatomical and molecular mediators of cough. (a) The cough cascade can be triggered in the airway by activation of vagal sensory neurons originating from the jugular and nodose ganglia. Airway sensory nerve activation results in an action potential being carried along the vagus nerve to the central nervous system via projections to the brain stem, specifically at the nTS and the Pa5. Release of neurotransmitters by these primary afferents can activate reflex pathways controlling respiratory muscles to evoke involuntary cough and/or second‐order neurons projecting to higher brain regions that evoke behavioral cough or sensations of an urge to cough. (b) Stimulation and activation of airway sensory neurons. Ion channels expressed by vagal sensory nerves respond to various chemical and mechanical stimuli to trigger depolarization of the plasma membrane. Influx of calcium may trigger sensory nerves to release neuropeptides. One action of neuropeptides may be to bind to receptors on epithelial cells (e.g., NK‐1), inducing release of proinflammatory mediators. Ion channels can also be found on airway epithelial cells, where stimulation can lead to calcium influx that triggers release of inflammatory mediators that may perpetuate further sensory nerve activation. Although the underlying mechanisms are not precisely known, ATP can be released through pannexin channels and activate P2X3 channels, leading to cell depolarization. Cumulative depolarization of a sufficient magnitude can trigger the opening of NaVs expressed by sensory nerves, leading to generation of an action potential carried through the vagus nerve to the central nervous system. (c) Action potentials carried by vagal afferents can trigger the release of glutamate to activate postsynaptic brain stem neurons via NMDA receptors. These afferent neurons may also release substance P, which can bind to NK‐1 receptors and propagate the signal leading to cough. α7 nAChR agonists may play a role in cough via expression on separate neurons which, when activated, release GABA to inhibit the postsynaptic brain stem neuron, thereby halting the cough cascade. The actual CNS sites of action of therapies for chronic cough may be different and more complex than depicted, and the mechanism of action in chronic cough for some therapies (e.g., gabapentin, amitriptyline/nortriptyline) are not currently well known. ATP, adenosine triphosphate; Ca²⁺, calcium; CNS, central nervous system; GABA, γ‐aminobutyric acid; Glu, glutamate; GPCR, G protein–coupled receptor; nAChR, nicotinic acetylcholine receptor; NaV, voltage‐gated sodium channel; NA+, sodium; NK‐1, neurokinin‐1 receptor; NMDA, N‐methyl‐D‐aspartate receptor; nTS, nucleus of the solitary tract; Pa5, paratrigeminal nucleus; P2X, ATP‐gated (purine) cation channel subtype 3 and 2/3; SP, substance P; TRP, transient receptor potential; TRPA, TRP ankyrin; TRPM, TRP melastatin; TRPV, TRP vanilloid.