Gabapentin vs. Benzonatate vs. Standard of Care for Cough in ILD

Cough in ILD Across ILD subtypes and geographic regions, dyspnoea on exertion and chronic cough are the most commonly reported symptoms. Chronic cough, defined by duration ≥ 8 weeks is the most common symptom in ILD. Cough is typically dry, persistent, and often disproportionate to radiological disease extent. In western studies, prevalence of among ILD subtypes was variable and the ILD subtype but is particularly prominent in IPF (83%) and HP (84%) compared to sarcoidosis where only 30-50% patients reports complaint of cough.

Impact of Cough on Quality of Life Chronic cough in ILD has a profound negative impact on health-related quality of life. Beyond physical discomfort, cough interferes with sleep, social interaction, communication, and emotional well-being. Studies using validated cough-specific instruments, such as the Leicester Cough Questionnaire, have demonstrated strong associations between cough severity and reduced quality-of-life scores. In patients with fibrotic ILD, cough-related quality-of-life impairment has also been linked to disease progression and poorer clinical outcomes, underscoring its relevance as a clinically meaningful symptom.

Current Recommendations for Management of Cough in ILD The management of cough in ILD remains challenging, as robust, ILD-specific evidence is limited. Current recommendations emphasize a systematic approach, beginning with optimization of treatment for the underlying ILD and identification of potentially reversible contributors such as gastro-oesophageal reflux, upper airway disease, infection, or medication-related cough. Pharmacological treatment recommended are thalidomide in IPF and gabapentin in refractory cough however the these are mostly by low quality evidence and expert consensus.

Gabapentin Gabapentin is a gabapentinoid originally developed as an antiepileptic agent and widely used for neuropathic pain. It binds to the α2δ subunit of voltage-gated calcium channels, leading to reduced excitatory neurotransmitter release and modulation of neuronal hyperexcitability. Chronic cough is increasingly understood as a manifestation of cough reflex hypersensitivity. Gabapentin is thought to suppress cough by attenuating central neural sensitization within the cough reflex pathway, thereby reducing abnormal afferent signalling and cough frequency. Randomized controlled trials in patients with chronic refractory cough have demonstrated that gabapentin significantly improves cough-specific quality of life and reduces cough severity compared with placebo. Although these studies were not ILD-specific, the findings have informed guideline recommendations and clinical practice, leading to cautious off-label use of gabapentin in patients with ILD-associated refractory cough.

Interstitial lung diseases (ILDs) are a group of heterogeneous disorders of the lung parenchyma characterized by inflammation and/or fibrosis resulting in dyspnoea and cough along with other symptoms and complications. In a study from 3089 patients of ILD from India, the crude prevalence of ILD in Northern Indians was 49.0-98.1, respectively per 100,000 population.

Chronic cough, defined by duration ≥ 8 weeks in a common symptom in ILD with a prevalence varying from 30% - 80% among various types. A 2018 study of 803 patients with ILD reported cough as the most common symptom with a prevalence of 86%. Currently, there is no FDA approved treatment for cough in ILD although various treatment strategies have been studied of which some are recommended by scientific societies which reflects lacunae in the evidence for treatment of cough in ILD.

It has been demonstrated that the sensitivity of the cough reflex is heightened in chronic cough. This has opened a new modality of neuromodulation-based treatment for chronic cough. Gabapentin is a gamma-aminobutyric acid (GABA) analogue that binds to the α2δ subunit of voltage-gated calcium channels of neurons and was initially introduced as an anti-seizure medication. A study by Ryan et al. showed significant relief in chronic cough with gabapentin, albeit this was a small study with a heterogeneous study population and not focused on ILD. A recent meta-analysis has also shown benefit with gabapentin in chronic cough treatment.

Benzonatate, initially used for cough suppression in 1958, represents another possible treatment option. It acts by anesthetizing the vagal stretch receptors in the lungs and pleura, thereby reducing the activation of the cough reflex at its origin. Benzonatate is a non-opioid antitussive structurally related to local anaesthetics. It exerts its antitussive effect primarily through peripheral mechanisms by anesthetizing stretch receptors in the respiratory tract and pleura, thereby dampening vagal afferent input to the cough center. Evidence supporting the use of benzonatate in chronic cough is limited. Small experimental studies suggest that it may reduce cough reflex sensitivity, particularly in acute cough settings. However, controlled clinical data demonstrating sustained benefit in chronic or ILD-related cough are sparse, and its role is generally confined to symptomatic relief rather than disease-modifying therapy. However, no clinical trial has shown its effectiveness in ILD.

Absence of a clear standard of care and approved drug for chronic cough, the commonest symptom in ILD, calls for further research in this area.

In this study, the investigators aim to compare gabapentin and benzonatate treatment with the standard of care for treating chronic cough in ILD. The investigators hypothesize that both gabapentin and benzonatate will be more effective than standard of care in treating chronic cough in ILD.