Elsevier

The Lancet

Volume 380, Issue 9853, 3–9 November 2012, Pages 1583-1589
The Lancet

Articles
Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(12)60776-4Get rights and content

Summary

Background

Refractory chronic cough causes substantial symptoms and quality-of-life impairment. Similarities between central reflex sensitisation in refractory chronic cough and neuropathic pain suggest that neuromodulators such as gabapentin might be effective for refractory chronic cough. We established the efficacy of gabapentin in patients with refractory chronic cough.

Methods

This randomised, double-blind, placebo-controlled trial was undertaken at an outpatient clinic in Australia. Adults with refractory chronic cough (>8 weeks' duration) without active respiratory disease or infection were randomly assigned to receive gabapentin (maximum tolerable daily dose of 1800 mg) or matching placebo for 10 weeks. Block randomisation was done with randomisation generator software, stratified by sex. Patients and investigators were masked to assigned treatment. The primary endpoint was change in cough-specific quality of life (Leicester cough questionnaire [LCQ] score) from baseline to 8 weeks of treatment, analysed by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000248369.

Findings

62 patients were randomly assigned to gabepentin (n=32) or placebo (n=30) and ten patients withdrew before the study end. Gabapentin significantly improved cough-specific quality of life compared with placebo (between-group difference in LCQ score during treatment period 1·80, 95% CI 0·56–3·04; p=0·004; number needed to treat of 3·58). Side-effects occurred in ten patients (31%) given gabapentin (the most common being nausea and fatigue) and three (10%) given placebo.

Interpretation

The treatment of refractory chronic cough with gabapentin is both effective and well tolerated. These positive effects suggest that central reflex sensitisation is a relevant mechanism in refractory chronic cough.

Funding

National Health and Medical Research Council of Australia and Hunter Medical Research Institute, Newcastle, Australia.

Introduction

Chronic cough is a common clinical problem for 11–16% of the population,1 affecting physical, psychological, and social domains of health.2 Although many patients are treated successfully,3 cough can persist even after extensive investigation or treatment trials in 20–42% of outpatient referrals. These patients have refractory chronic cough.4, 5

The sensitivity of the cough reflex is increased in chronic cough.4, 6 Hypersensitivity to tussive stimuli such as capsaicin is caused by both peripheral and central mechanisms. Non-tussive stimuli can also trigger cough, which suggests that additional central neuronal mechanisms or central reflex sensitisation are implicated. Peripheral sensitisation (cough reflex hypersensitivity in peripheral nerves) has been shown with enhanced cough responses to inhaled capsaicin4, 6 and increased neural expression of transient receptor potential receptors. The role of central sensitisation in refractory cough has received little attention; however, refractory cough shares similarities with other disorders associated with central sensitisation, such as neuropathic pain.7

The clinical features that indicate central sensitisation in chronic pain, such as paraesthesia (abnormal sensation in the absence of a stimulus), hyperalgesia (pain triggered by a low exposure to a known painful stimulus), and allodynia (pain triggered by a non-painful stimulus), show similarities with the clinical features of refractory chronic cough, such as an abnormal throat sensation or tickle (laryngeal paraesthesia), increased cough sensitivity in response to known tussigens (hypertussia), and cough triggered in response to non-tussive stimuli such as talking or cold air (allotussia).8

The neuromodulator gabapentin is effective for neuropathic pain with central sensitisation, and findings from two case series have shown success with gabapentin in chronic cough.9, 10 We aimed to test whether gabapentin, given to patients with refractory chronic cough, improves cough-specific quality of life and decreases cough severity and frequency.

Section snippets

Study design and participants

In this randomised, double-blind, placebo-controlled trial, we recruited adults with chronic cough lasting longer than 8 weeks from the John Hunter Hospital respiratory outpatient clinic (New Lambton, NSW, Australia), which receives referrals from primary and secondary care. Recruitment took place between October, 2008, and September, 2010. All participants had negative responses to previous investigations or trials of treatments for asthma, gastro-oesophageal reflux disease, and rhinitis

Results

We recruited 65 patients diagnosed with refractory chronic cough. We excluded three patients and randomly assigned the remaining 62 to either gabapentin (n=32) or placebo (n=30). Ten participants withdrew from the study and 52 completed it (gabapentin, n=26; placebo, n=26; figure 1), although one in the placebo group did not receive the full dose of the study drug due to a pharmacy dispensing error.

All patients had received several treatment trials before study entry and their cough was

Discussion

Findings from this trial have shown that gabapentin significantly improved cough-specific quality of life compared with placebo. These results suggest that gabapentin might be an effective therapy for refractory chronic cough (panel).

The onset of action of gabapentin was within 4 weeks, and the effect was maintained during maximal dosing at 8 weeks. However, the improvement in cough-specific quality of life (LCQ score) was not sustained after treatment withdrawal and LCQ score returned to

References (30)

  • A Vertigan et al.

    Voice and upper airway symptoms in people with chronic cough and paradoxical vocal fold movement

    J Voice

    (2007)
  • JM Reich

    Chronic idiopathic cough: self-sustaining?

    Chest

    (2007)
  • RW Bastian et al.

    Sensory neuropathic cough: a common and treatable cause of chronic cough

    Otolaryngol Head Neck Surg

    (2006)
  • SM Greene et al.

    Evidence for sensory neuropathy and pharmacologic management

    Otolaryngol Clin North Am

    (2010)
  • AC Ford et al.

    Cough in the community: a cross sectional survey and the relationship to gastrointestinal symptoms

    Thorax

    (2006)
  • Cited by (371)

    • Cough medicines for children- time for a reality check

      2023, Paediatric Respiratory Reviews
    View all citing articles on Scopus
    View full text