Pregabalin and Speech Pathology Combination Therapy for Refractory Chronic Cough: A Randomized Controlled Trial

doi:10.1378/chest.15-1271

Chest

Volume 149, Issue 3, March 2016, Pages 639-648

https://doi.org/10.1378/chest.15-1271 Get rights and content

Background

Chronic refractory cough (CRC) is a difficult problem to treat. Speech pathology treatment (SPT) improves symptoms but resolution is incomplete. Centrally acting neuromodulators also improve cough symptoms, but not cough reflex sensitivity, and the effect is short-lived. We hypothesized that combined SPT and centrally acting neuromodulators would have a superior outcome than SPT alone. Our goal was to determine whether combined pregabalin and SPT is more effective than SPT alone.

Methods

Randomized placebo controlled trial. Forty patients with CRC were randomly assigned to receive either combined SPT and pregabalin 300 mg daily or combined SPT and placebo. Outcome measures were collected at baseline, end of treatment, and 4 weeks after the end of treatment. Primary outcome measures were cough frequency using the Leicester Cough Monitor, cough severity using a visual analog scale (coughVAS), and cough-related quality of life (QOL) using the Leicester Cough Questionnaire (LCQ).

Results

Cough severity, cough frequency, and cough QOL improved in both groups. The degree of improvement in LCQ and coughVAS was greater with combined SPT and pregabalin than SPT alone; the mean difference in LCQ was 3.5, 95%CI of difference 1.1 to 5.8; the mean difference in coughVAS was 25.1, 95% CI of difference 10.6 to 39.6. There was no significant difference in improvement in cough frequency between groups. There was no deterioration in symptoms once pregabalin was withdrawn. Median capsaicin cough sensitivity improved from 15.7 to 47.5 μM with combined SPT and pregabalin and from 3.92 to 15.7 μM with SPT alone.

Conclusions

Combined SPT and pregabalin reduces symptoms and improves QOL compared with SPT alone in patients with CRC.

Section snippets

Methods

This study was a randomized, double-blind, placebo (PLAC)-controlled trial that was approved by the Hunter New England Research Ethics Committee (approval number 11/11/16/3.04) and registered with the Australian and New Zealand clinical trials register (12611001186943). All participants gave written informed consent.

Results

We screened 114 people with chronic cough between March 2012 and June 2014 and randomized 40 who met the study inclusion criteria of CRC of more than 8 weeks’ duration (Table 2). Twenty participants were randomized to each group, with 17 completing treatment in the SP + PREG group and 18 in the SP + PLAC group (Fig 2). Reasons for noncompletion are reported in Figure 2. The mean duration of cough was 123 months (SD, 119; range, 3-480). Pretreatment values were similar between groups for the

Discussion

This randomized, controlled trial demonstrated that when SPT is combined with the neuromodulator PREG, there is a significantly greater improvement in perceived cough severity and cough QOL than with SPT alone. Cough reflex sensitivity was improved by the addition of SP to PREG, which is significant because gabapentin, a similar agent to PREG, did not improve cough reflex sensitivity.⁷ The magnitude of the urge to cough at the end of capsaicin cough sensitivity testing was also reduced in both

Conclusion

Combined SPT and PREG is beneficial in reducing symptoms in CRC. Although it causes some adverse effects, these resolve upon drug cessation. When PREG is used in combination with SPT, the beneficial effects continue for at least 4 weeks after cessation of PREG. These results are consistent with the emerging concepts of sensory hyperresponsiveness as a mechanism of CRC.

Acknowledgments

Author contributions: A. E. V. takes responsibility for the content of the manuscript, including the data and analysis;was the study coordinator, designed, supervised, and provided the speech pathology treatment; conducted data analysis; and drafted the paper. S. L. K. provided the speech pathology treatment, conducted the capsaicin cough testing, and analyzed cough monitor data. N. M. R. conducted capsaicin cough testing and analyzed cough monitor data. S. S. B. consulted on the cough monitor

References (27)

R. Haque et al.
Chronic idiopathic cough: A discrete clinical entity?
Chest
(2005)
A.E. Vertigan et al.
Chronic refractory cough as a sensory neuropathy: evidence from a reinterpretation of cough triggers
J Voice
(2011)
K. Chung et al.
Prevalence, pathogenesis and causes of chronic cough
Lancet
(2008)
K.F. Chung et al.
Chronic cough as a neuropathic disorder
Lancet Respir Med
(2013)
N. Ryan et al.
Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial
Lancet
(2012)
I. Pavord et al.
Management of chronic cough
Lancet
(2008)
P. Dicpinigaitis
Short- and long-term reproducibility of capsaicin cough challenge testing
Pulm Pharmacol Ther
(2003)
S.S. Birring et al.
Cough frequency, cough sensitivity and health status in patients with chronic cough
Respir Med
(2006)
A. Vertigan et al.
Efficacy of speech pathology management for chronic cough: a randomised, single blind, placebo controlled trial of treatment efficacy
Thorax
(2006)
S. Chamberlain et al.
Cough suppression therapy: Does it work?
Pulm Pharmacol Ther
(2013)

A. Morice et al.

Opiate therapy in chronic cough

Am J Respir Crit Care Med

(2007)

S. Halum et al.

A new treatment option for laryngeal sensory neuropathy

Laryngoscope

(2009)

N. Ryan et al.

Chronic cough and laryngeal dysfunction improve with specific treatment of cough and paradoxical vocal fold movement

Cough

(2009)

Cited by (187)

Safety and efficacy of P2X3 receptor antagonist for the treatment of refractory or unexplained chronic cough: A systematic review and meta-analysis of 11 randomized controlled trials
2023, Pulmonary Pharmacology and Therapeutics
Chronic refractory cough is a challenging condition that requires a thorough evaluation and management approach. P2X3 receptors that are ATP-dependent play an important part in nerve fiber sensitization and pathological pain pathways. We conducted this systematic review and meta-analysis to determine the long-term safety and efficacy of P2X3 receptor antagonist drugs in chronic cough.
We systematically searched PubMed, Scopus, Web of Science, and Embase to identify all relevant published studies through January 15, 2023 that assessed P2X3 antagonists in chronic cough. The protocol was registered in the PROSPERO database with ID: CRD42023422408. Efficacy outcomes were awake (daytime) cough frequency, night cough frequency, 24-h cough frequency, Cough Severity Diary, and total Leicester Cough Questionnaire score. We used the random-effect model to pool the data using RStudio and CMA software.
A total of 11 randomized controlled trials comprising 1350 patients receiving a p2x3 antagonist compared to the placebo group were included in this meta-analysis. A significant decrease in 24-h cough frequency (MD = −4.99, 95% CI [−7.15 to −2.82], P < 0.01), awake (daytime) cough frequency (MD = −7.18, 95% CI [−9.98 to 4.37], P < 0.01), and total Leicester Cough Questionnaire score (MD = 1.74, 95% CI [1.02 to 2.46], P < 0.01) exhibited between the P2X3 antagonist and placebo groups. The frequency of the night cough showed an insignificant difference between the two groups. According to the safety, drug-related adverse events, dysgeusia, hypogeusia, and ageusia significantly increased between the P2X3 antagonist and placebo groups.
P2X3 receptor antagonists are promising drugs for treating chronic cough by significantly reducing the frequency, severity, and quality. Some potential side effects may include drug-related adverse events such as hypogeusia, ageusia, and dysgeusia.
Predictors of treatment response to pregabalin in unexplained or refractory chronic cough
2023, Respiratory Medicine
Patients with chronic cough (>8 weeks) often remain symptomatic after appropriate investigations and therapeutic trials. Prior research has shown a benefit in certain individuals from pregabalin, but clinical improvement is quite unpredictable and variable.
The main objective of this study was to identify the demographic and clinical characteristics associated with a higher likelihood of cough improvement with a trial of pregabalin therapy.
50 consecutive patients with chronic cough were enrolled in this prospective cohort study. Subjects were prescribed pregabalin 75 mg oral qhs for 4 weeks followed by 75 mg oral bid. Leicester Cough Questionnaire (LCQ) was completed at treatment initiation and after 3 months of therapy. A comparison was performed between treatment responders (LCQ total score improvement ≥1.3) and non-responders.
56% of patients reported a LCQ total score improvement ≥1.3 (minimal clinically important difference). Responders to pregabalin therapy were more likely to have refractory (with underlying pulmonary disease) versus unexplained chronic cough (p = 0.01). Patients with significant improvement were also on average more symptomatic at baseline (mean LCQ total score 10.2 versus 13.0, p < 0.01). No significant relationship was identified with age, gender, body mass index, history of anxiety and/or depression, cigarette smoking history, or cough duration (p > 0.05). The unexplained chronic cough group had a strong female predominance (85.7% versus 40.9% for refractory cough, p < 0.01).
This is the first study that has investigated clinical predictors of treatment response to pregabalin in chronic cough patients. Further research is needed to develop therapies for subjects who do not improve with currently available neuromodulating medications.
Cough Severity Index: Validation in Brazilian Portuguese
2023, Journal of Voice
To develop a validity profile for the cough severity index in the Brazilian Portuguese language (CSI-Br).
The study sample consisted of 100 participants divided into Chronic Cough Group (CG; 50 individuals with a mean age of 46.4; standard deviation [SD]: 11.7) and Healthy Control Group (HCG; 50 individuals with a mean age of 33.0 [SD: 12.3]). The data collection procedures were as follows: (a) application of CSI-Br for all participants; (b) application of the Voice Handicap Index (VHI)-10 and the Newcastle Laryngeal Hypersensitivity Questionnaire (LHQ-Br) in the CG; (c) application of CSI-Br for test-retest reliability with an interim of between 2-14 days. The CSI-Br validation was composed of five stages: construct validity, reliability, reproducibility, convergent validity, and discriminant validity.
In construct validity, the instrument identified two factors and explained 67.6% of the total variance. The reliability had a value of a=0.914. Reproducibility showed an ICC value of 0.909. CSI-Br showed a negative correlation with VHI-10 and a positive correlation with LHQ-Br in convergent validity. In discriminant validity, all items and factors differentiated participants in the CG from those in the HCG.
The ten-item CSI-Br with two factors is reliable and valid for analyzing the severity of chronic cough symptoms in Brazilian individuals.
Management of non-pharmacologic therapy for chronic refractory cough: Mechanism, composition, applicable population, and assessment
2023, Heliyon
Chronic cough is common in the clinic and can seriously affect the quality of life of patients. Following the existing guidelines for treatment, refractory chronic cough is defined as a clinical condition in which the cause of the cough remains unclear after comprehensive examination and treatment, or the cause is clear but symptomatic treatment is ineffective.
It has been found that non-pharmacologic therapy can effectively improve the quality of life and reduce the frequency of coughing for some patients with refractory chronic cough. Compared with pharmacological therapy, non-pharmacologic therapy has no obvious adverse effects; therefore, non-pharmacologic therapy has good application prospects in the diagnosis and treatment of refractory chronic cough. This paper summarizes the composition, indication, action and mechanism of non-pharmacologic therapy in the diagnosis and treatment of refractory chronic cough and prospects for research on non-pharmacologic therapy.
Cough and cough hypersensitivity as treatable traits of asthma
2023, The Lancet Respiratory Medicine
Cough is a common and troublesome symptom in people with asthma and is often associated with poorer asthma control and exacerbations. Apart from asthma, other causes or comorbidities might underlie cough in asthma, such as rhinosinusitis and bronchiectasis. Eosinophilic inflammation and bronchoconstriction can lead to an acute episode of cough or worsen chronic cough. Cough hypersensitivity with laryngeal paraesthesia, allotussia, and hypertussia might underlie the cough of asthma through augmented sensory nerve excitability of upper-airway vagal sensory nerves. Cough associated with bronchoconstriction and type 2 inflammation should respond to inhaled corticosteroids and long-acting β-adrenoceptor agonist therapy. For cough hypersensitivity in adults, speech and language therapy and neuromodulators (eg, gabapentin) could be considered. In children, there is no consistent association of asthma with cough sensitivity or between cough and asthma severity. Further research is needed to realise the potential of cough as a measure of asthma control, to understand the mechanisms of cough in asthma, and to develop safe, effective treatments and a precision-medicine approach to the management of cough in asthma in children and adults.
Guidelines for the management of chronic cough in adults. Endorsed by the French speaking society of respiratory diseases (Société de Pneumologie de Langue Française, SPLF), the Société Française d'Oto-Rhino-Laryngologie et de Chirurgie de la Face et du Cou (SFORL), the Société Française de Phoniatrie et de Laryngologie (SFPL), the Société Nationale Française de Gastro-entérologie (SNFGE)
2023, Respiratory Medicine and Research
Patients with chronic cough experience a high alteration of quality of life. Moreover, chronic cough is a complex entity with numerous etiologies and treatments. In order to help clinicians involved in the management of patients with chronic cough, guidelines on chronic cough have been established by a group of French experts. These guidelines address the definitions of chronic cough and the initial management of patients with chronic cough. We present herein second-line tests that might be considered in patients with cough persistence despite initial management. Experts also propose a definition of unexplained or refractory chronic cough (URCC) in order to better identify patients whose cough persists despite optimal management. Finally, these guidelines address the pharmacological and non-pharmacological interventions useful in URCC. Thus, amitryptilline, pregabalin, gabapentin or morphine combined with speech and/or physical therapy are a mainstay of treatment strategies in URCC. Other treatment options, such as P2 × 3 antagonists, are being developed.

View all citing articles on Scopus

: FUNDING/SUPPORT: This project was supported by the Division of Medicine, John Hunter Hospital, and National Health and Medical Research Council project grant. Prof Gibson is supported by a National Health and Medical Research Council Practitioner Research Fellowship. Dr Ryan was supported by a John Hunter Hospital Charitable Trust Award [G1300784].

View full text

Chest

Original Research: Signs and Symptoms of Chest DiseasesPregabalin and Speech Pathology Combination Therapy for Refractory Chronic Cough: A Randomized Controlled Trial

Background

Methods

Results

Conclusions

Section snippets

Methods

Results

Discussion

Conclusion

Acknowledgments

Chest

J Voice

Lancet

Lancet Respir Med

Lancet

Lancet

Pulm Pharmacol Ther

Respir Med

Efficacy of speech pathology management for chronic cough: a randomised, single blind, placebo controlled trial of treatment efficacy

Thorax

Cough suppression therapy: Does it work?

Pulm Pharmacol Ther

Opiate therapy in chronic cough

Am J Respir Crit Care Med

A new treatment option for laryngeal sensory neuropathy

Laryngoscope

Chronic cough and laryngeal dysfunction improve with specific treatment of cough and paradoxical vocal fold movement

Cough

Original Research: Signs and Symptoms of Chest Diseases
Pregabalin and Speech Pathology Combination Therapy for Refractory Chronic Cough: A Randomized Controlled Trial