We searched PubMed for peer-reviewed research published in English between Jan 1, 1980, and Jan 31, 2013, using the search term “cough” in combination with “neuropathic” and “hypersensitivity”. We also drew on accumulated publications gathered through our involvement in cough research and treatment during the past 20 years.
Personal ViewChronic cough as a neuropathic disorder
Introduction
Cough is a common symptom in patients with a range of respiratory and non-respiratory diseases, and it has been subdivided into acute and chronic cough dependent on duration. An acute cough that lasts for less than 3 weeks is self-limiting and typically secondary to an upper-respiratory-tract infection, whereas a cough that persists for more than 8 weeks is termed chronic, and often the symptom has persisted for much longer than 8 weeks by the time of presentation. Whereas acute, self-limiting cough remains a disorder for which supportive measures are adequate, chronic cough, which can persist for months and years, is a difficult clinical problem largely because of poor understanding of the pathophysiological processes involved and the absence of effective antitussive therapies. Results of some epidemiologic studies1, 2, 3, 4 suggest that chronic cough is very prevalent in the community (9–33%) and could be increasing in association with rising environmental pollution. Many patients seek medical advice because a chronic cough can seriously impair quality of life.5 Although a cause for the cough can be apparent in most patients, in a substantial proportion (ranging from 7% to 40%) no underlying cause can be identified and the cough is referred to as idiopathic or unexplained.1 Irrespective of whether or not the cause can be identified, the most consistent pathophysiological finding in patients with chronic cough is an abnormal upregulation of the cough reflex, manifest by heightened tussive responses to citric acid or capsaicin inhalation (figure 1).6, 7 This idea of cough hypersensitivity is gaining broader recognition among physicians, but so far little explanation for this important clinical notion has been suggested. In this Personal View, we argue that cough hypersensitivity arises from a neuropathic disorder that affects the cough afferent pathways.
Section snippets
Chronic cough as a neuropathic process
A persistent or intermittent tickling, irritating sensation, rawness in the pharynx or laryngeal area (sometimes referred to as a feeling of an itch), a choking sensation in the throat, or, less often, a sensation in the chest, can be reported by patients with chronic cough. These sensations result in an urge to cough and often precede the uncontrollable paroxysms of coughing that are typical of chronic cough. Other symptoms include repeated throat clearing, chest tightness, hoarse voice and
Afferent cough pathways: peripheral to central
Coughing is both a reflex that requires minimum conscious control and a voluntary behaviour either with or without an accompanying sensory awareness of the need to cough.18, 19, 20, 21, 22, 23 Activation of peripheral sensory nerves is usually the initiating factor that drives the resultant cough, but the outcome can be either reflexive cough with minimum conscious involvement or behavioural cough secondary to the perception of an urge to cough. Reflex cough, behavioural cough, and the urge to
Mechanisms of cough hypersensitivity
Several features of the cough neural circuitry probably contribute to the development of afferent-nerve-dependent cough in disease (figure 2). First, afferent nerves are highly susceptible to sensitisation by various neuroactive molecules that change the activation characteristics of cough afferents and allow appropriate afferent encoding in response to irritant stimuli. These molecules can also change in terms of their constituents and concentrations, which perhaps underlies the manifestation
Can cough hypersensitivity result from neuropathology?
If cough hypersensitivity manifests from altered activity of one or more of the components of the cough neural circuitry, then is this altered activity a result of a neuropathic disorder (table)? The first step towards answering this question is to define how neuropathic cough might differ from normal physiological cough responses. The approach that has worked well for pain researchers has been to define pain as nociceptive, inflammatory, or neuropathic; this strategy differentiates the
Inflammatory factors and neurogenic mechanisms
Chronic cough is often associated with airway inflammation and remodelling.63 Damaged bronchial epithelium, basement-membrane thickening, and a chronic inflammatory infiltrate have been described in airway biopsy samples from patients with unexplained chronic cough.64, 65 In bronchial biopsy studies of chronic cough,65 an increase in the number of mast cells together with features of airway-wall remodelling (characterised by an increase in vascular profiles, subepithelial fibrosis, and
Respiratory viruses and cough: a neuropathic link?
Respiratory viral infections are typically accompanied by an acute cough, which can persist for weeks or months in some patients. Experimental models of rhinovirus infection have shown cough-reflex hypersensitivity to chemical86, 87 and mechanical stimulation.88 Virus-induced neuropathic change has been described in post-herpetic neuralgia caused by reactivation of varicella zoster virus in trigeminal sensory neurons. Because this disorder is characterised clinically by hyperalgesia (heightened
Evidence from antitussive therapies
The success of drugs used to treat chronic pain, such as amitriptyline and gabapentin, as antitussives also lends support to the notion of chronic cough as a neuropathic disorder. In 12 patients treated with amitriptyline, 11 had prompt, substantial reduction of their cough.92 In a prospective, randomised, controlled, open-label trial to compare the effectiveness of amitriptyline with codeine plus guaifenesin for chronic cough with suspected post-viral vagal neuropathy, most patients in the
What is the missing link to neuropathic cough?
The proposition that the hypersensitivity syndrome that encompasses most chronic cough is a neuropathic disorder is well supported by empirical evidence, and we have compared cough hypersensitivity with pain hypersensitivity to provide evidence for cough-pathway neuropathy. Indeed, the physiological and pathophysiological similarities between cough and pain are easily recognised,113, 114 and the evidence presented supports our assertions of a mechanistically comparable neuropathy. This
Search strategy and selection criteria
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Functional neuroanatomy of human voluntary cough and sniff production
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Voluntary and reflex cough: similarities and differences
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Neuroscience
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Brain Res
Caudal nuclei of the rat nucleus of the solitary tract differentially innervate respiratory compartments within the ventrolateral medulla
Neuroscience
Allergen-induced substance P synthesis in large-diameter sensory neurons innervating the lungs
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Modulation of experimentally-induced cough by stimulation of nasal mucosa in cats and guinea pigs
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Neuroscience
Combined application of excitatory amino acids and substance P produces long-lasting changes in responses of primate spinothalamic tract neurons
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Deficiency in endogenous modulation of prolonged heat pain in patients with irritable bowel syndrome and temporomandibular disorder
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An fMRI study of cerebral processing of brush-evoked allodynia in neuropathic pain patients
Neuroimage
Deconstructing the neuropathic pain phenotype to reveal neural mechanisms
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Airway inflammation and remodelling changes in patients with chronic cough: do they tell us about the cause of cough?
Pulm Pharmacol Ther
Nature of airway inflammation and remodeling in chronic cough
J Allergy Clin Immunol
Phosphoinositide-3-kinase and mitogen activated protein kinase signaling pathways mediate acute NGF sensitization of TRPV1
Mol Cell Neurosci
Effect of viral upper respiratory tract infection on the urge-to-cough sensation
Respir Med
Cough induced by airway vibration as a model of airway hyperreactivity in patients with acute upper respiratory tract infection
Pulm Pharmacol Ther
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Sensory neuropathic cough: a common and treatable cause of chronic cough
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Lancet
Site- and test-dependent antinociceptive efficacy of amitriptyline in rats
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Long-term ambient air pollution and respiratory symptoms in adults (SAPALDIA study)
Am J Respir Crit Care Med
Capsaicin cough sensitivity decreases with successful treatment of chronic cough
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Sensitivity of the cough reflex in patients with chronic cough
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Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24
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Acidification of the oesophagus acutely increases the cough sensitivity in patients with gastro-oesophageal reflux and chronic cough
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Neurosarcoidosis affecting the vagus nerve
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Cervical segment nervus vagus neurofibroma with associated neurofibromatosis type 1: a case report
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Cough reflex threshold in diabetes mellitus with and without autonomic neuropathy
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Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs
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Synergistic interactions between airway afferent nerve subtypes regulating the cough reflex in guinea-pigs
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Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea-pigs
J Physiol
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Gabapentin alleviated the cough hypersensitivity and neurogenic inflammation in a guinea pig model with repeated intra-esophageal acid perfusion
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2023, Respiratory Physiology and Neurobiology