Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: A double-blind randomized controlled trial

doi:10.1016/j.jaci.2014.01.038

Journal of Allergy and Clinical Immunology

Volume 134, Issue 1, July 2014, Pages 56-62.e4

https://doi.org/10.1016/j.jaci.2014.01.038 Get rights and content

Background

Inhalation of capsaicin, the extract of hot chili peppers, induces coughing in both animals and human subjects through activation of transient receptor potential vanilloid 1 (TRPV1) on airway sensory nerves. Therefore the TRPV1 receptor is an attractive target for the development of antitussive agents.

Objective

We sought to assess the antitussive effect of TRPV1 antagonism in patients with refractory chronic cough.

Methods

Twenty-one subjects with refractory chronic cough (>8 weeks) attending a specialist clinic were recruited to a randomized, double-blind, placebo-controlled crossover trial assessing a TRPV1 antagonist (SB-705498). Cough reflex sensitivity to capsaicin (concentration of capsaicin inducing at least 5 coughs) and 24-hour cough frequency were coprimary end points assessed after a single dose of SB-705498 (600 mg) and matched placebo. Cough severity and urge to cough were reported on visual analog scales, and cough-specific quality of life data were also collected.

Results

Treatment with SB-705498 produced a significant improvement in cough reflex sensitivity to capsaicin at 2 hours and a borderline significant improvement at 24 hours compared with placebo (adjusted mean difference of +1.3 doubling doses at 2 hours [95% CI, +0.3 to +2.2; P = .0049] and +0.7 doubling doses at 24 hours [95% CI, +0.0 to +1.5; P = .0259]). However, 24-hour objective cough frequency was not improved compared with placebo. Patient-reported cough severity, urge to cough, and cough-specific quality of life similarly suggested no effect of SB-705498.

Conclusion

This study raises important questions about both the role of TRVP1-mediated mechanisms in patients with refractory chronic cough and also the predictive value of capsaicin challenge testing in the assessment of novel antitussive agents.

Section snippets

Methods

Detailed methods are provided in the Methods section in this article's Online Repository at www.jacionline.org.

Subjects

Patients' characteristics are summarized in Table I. The majority of subjects were female and middle aged, as is typical of patients presenting with refractory cough. At screening, subjects were highly sensitive to capsaicin; the median capsaicin C5 value was 7.81 μmol/L (range, 0.49-125 μmol/L). Of 21 patients screened and randomized, 2 withdrew after the first treatment period because of symptoms consistent with a viral upper respiratory tract infection. Both patients had received placebo

Discussion

To the best of our knowledge, this is the first study to assess a TRPV1 receptor antagonist as an antitussive agent in patients. Despite clear evidence of TRPV1 antagonism in the airways, with a significant reduction in experimentally induced cough responses to capsaicin with SB-705498 treatment, this did not translate into any significant improvement in spontaneous cough frequency. Patient reports of cough severity, urge to cough, and cough-specific quality of life similarly suggested no

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Cited by (155)

TRPV1: Receptor structure, activation, modulation and role in neuro-immune interactions and pain
2024, Cell Calcium
In the 1990s, the identification of a non-selective ion channel, especially responsive to capsaicin, revolutionized the studies of somatosensation and pain that were to follow. The TRPV1 channel is expressed mainly in neuronal cells, more specifically, in sensory neurons responsible for the perception of noxious stimuli. However, its presence has also been detected in other non-neuronal cells, such as immune cells, β- pancreatic cells, muscle cells and adipocytes. Activation of the channel occurs in response to a wide range of stimuli, such as noxious heat, low pH, gasses, toxins, endocannabinoids, lipid-derived endovanilloid, and chemical agents, such as capsaicin and resiniferatoxin. This activation results in an influx of cations through the channel pore, especially calcium. Intracellular calcium triggers different responses in sensory neurons. Dephosphorylation of the TRPV1 channel leads to its desensitization, which disrupts its function, while its phosphorylation increases the channel's sensitization and contributes to the channel's rehabilitation after desensitization. Kinases, phosphoinositides, and calmodulin are the main signaling pathways responsible for the channel's regulation. Thus, in this review we provide an overview of TRPV1 discovery, its tissue expression as well as on the mechanisms by which TRPV1 activation (directly or indirectly) induces pain in different disease models.
Efficacy and safety of pharmacotherapy for refractory or unexplained chronic cough: a systematic review and network meta-analysis
2023, eClinicalMedicine
Refractory chronic cough (RCC) has a significant impact on patient’s health-related quality of life and represents a challenge in clinical management. However, the optimal treatment for RCC remains controversial. This study aimed to investigate and compare the efficacy and safety of the current pharmacological therapeutic options for RCC.
A systematic review was performed by searching PubMed, Web of Science, Embase, and Ovid databases from January 1, 2008 to March 1, 2023. All randomised control trials (RCTs) reporting outcomes of efficacy or/and safety were included in the Bayesian network meta-analysis. Here, we compared the effects on Leicester Cough Questionnaire (LCQ), Visual Analogue Scale (VAS), and objective cough frequency of patients with RCC. Besides, we also compared the incidence of adverse events (AEs) for analysis of safety. PROSPERO registration: CRD42022345940.
19 eligible RCTs included 3326 patients and 7 medication categories: P2X3 antagonist, GABA modulator, Transient Receptor Potential (TRP) modulator, NK-1 agonist, opioid analgesic, macrolide, and sodium cromoglicate. Compared with placebo, mean difference (MD) of LCQ and 24 h cough frequency for P2X3 antagonist relief were 1.637 (95% CI: 0.887–2.387) and −11.042 (P = 0.035). Compared with placebo, effect sizes (MD for LCQ and cough severity VAS) for GABA modulator were 1.347 (P = 0.003) and −7.843 (P = 0.003). In the network meta-analysis, gefapixant is the most effective treatment for patients with RCC (The Surface Under the Cumulative Ranking Curves (SUCRA) is 0.711 in LCQ, 0.983 in 24 h cough frequency, and 0.786 in cough severity VAS). Lesogaberan had better efficacy than placebo (SUCRA: 0.632 vs. 0.472) in 24 h cough frequency. Eliapixant and lesogaberan had better efficacy than placebo in cough severity VAS. However, TRP modulator had worse efficacy than placebo. In the meta-analysis of AEs, the present study found P2X3 antagonist had a significant correlation to AEs (RR: 1.129, 95% CI: 1.012–1.259), especially taste-related AEs (RR: 6.216, P < 0.05).
In this network meta-analysis, P2X3 antagonist showing advantages in terms of efficacy is currently the most promising medication for treatment of RCC. GABA modulator also showed potential efficacy for RCC but with AEs of the central system. Nevertheless, the role of TRP modulator needed to be revisited. Further research is needed to determine the potential beneficiary population for optimizing the pharmacological management of chronic cough.
National Natural Science Foundation of China (81870079), Guangdong Science and Technology Project (2021A050520012), Incubation Program of National Science Foundation for Distinguished Young Scholars (GMU2020-207).
Tiotropium for refractory cough in asthma via cough reflex sensitivity: A randomized, parallel, open-label trial
2023, Annals of Allergy, Asthma and Immunology
We previously reported in an uncontrolled study that tiotropium alleviated chronic cough in asthma refractory to inhaled corticosteroids and long-acting β2 agonists (ICS/LABA) by modulating capsaicin cough reflex sensitivity (C-CRS).
We sought to determine the antitussive effects of tiotropium for refractory cough in asthma in a randomized, parallel, open-label trial.
A total of 58 patients with asthma having chronic cough refractory to ICS/LABA were randomized in a 2:1 ratio to add tiotropium 5 μg (39 patients) or theophylline 400 mg (19 patients) for 4 weeks. Patients underwent workups, including capsaicin cough challenge test and subjective measures such as cough severity visual analog scales (VAS). We adopted C5, the lowest capsaicin concentration to induce at least 5 coughs, as an index of C-CRS. We also performed a posthoc analysis to identify factors predicting tiotropium responders, who found an improvement of at least 15 mm in cough severity VAS.
A total of 52 patients (tiotropium, 38; theophylline, 14) completed the study. Both tiotropium and theophylline significantly improved cough severity VAS and cough-specific quality of life. Tiotropium, but not theophylline, significantly increased C5, whereas pulmonary function did not change in either group. In addition, changes in cough severity VAS correlated with changes in C5 values in the tiotropium group. A posthoc analysis revealed that heightened C-CRS (C5 ≤1.22 µM) before the addition of tiotropium was an independent predictor for tiotropium responders.
Tiotropium may alleviate chronic cough in asthma refractory to ICS/LABA by modulating C-CRS. Heightened C-CRS may predict responsiveness to tiotropium for refractory cough in asthma.
Clinical Trials Registry ID: UMIN000021064 (https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000024253).
Transient Receptor Potential Channel Vanilloid 1 Contributes to Facial Mechanical Hypersensitivity in a Mouse Model of Atopic Asthma
2023, Laboratory Investigation
Sensitive skin, a common pathophysiological feature of allergic diseases, is defined as an unpleasant sensation in response to stimuli that normally should not provoke such sensations. However, the relationship between allergic inflammation and hypersensitive skin in the trigeminal system remains to be elucidated. To explore whether bronchial allergic inflammation affects facial skin and primary sensory neurons, we used an ovalbumin (OVA)–induced asthma mouse model. Significant mechanical hypersensitivity was observed in the facial skin of mice with pulmonary inflammation induced by OVA sensitization compared to mice treated with adjuvant or vehicle as controls. The skin of OVA-treated mice showed an increased number of nerve fibers, especially rich intraepithelial nerves, compared to controls. Transient receptor potential channel vanilloid 1 (TRPV1)–immunoreactive nerves were enriched in the skin of OVA-treated mice. Moreover, epithelial TRPV1 expression was higher in OVA-treated mice than in controls. Trigeminal ganglia of OVA-treated mice displayed larger numbers of activated microglia/macrophages and satellite glia. In addition, more TRPV1 immunoreactive neurons were found in the trigeminal ganglia of OVA-treated mice than in controls. Mechanical hypersensitivity was suppressed in OVA-treated Trpv1-deficient mice, while topical skin application of a TRPV1 antagonist before behavioral testing reduced the reaction induced by mechanical stimulation. Our findings reveal that mice with allergic inflammation of the bronchi had mechanical hypersensitivity in the facial skin that may have resulted from TRPV1-mediated neuronal plasticity and glial activation in the trigeminal ganglion.
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.
Gabapentin for chronic refractory cough: A system review and meta-analysis
2023, Heliyon
To evaluate the efficacy and safety of gabapentin in the treatment of chronic refractory cough by Meta-Analysis.
Literatures were retrieved from PubMed, Embase (OvidIP), Cochrane Library, CNKI, VIP, Wanfang Database and China Biomedical Management System and eligible prospective studies were screened. Data were extracted and analyzed by using RevMan 5.4.1 software.
Six articles (2 RCTs and 4 prospective studies) with 536 participants were finally included. Meta-analysis showed that gabapentin was better than placebo in cough-specific quality of life (LCQ score, MD = 4.02, 95%CI [3.26,4,78], Z = 10.34, P < 0.00001), cough severity (VAS score, MD = −29.36, 95% CI (-39.46, -19.26), Z = 5.7, P < 0.00001), cough frequency (MD = -29.87, 95% CI [- 43.84, -15.91], Z = 4.19, P < 0.0001) and therapeutic efficacy (RR = 1.37,95%CI [1.13,1.65], Z = 3.27, P = 0.001), and equal in safety (RR = 1.32,95%CI [0.47,3.7], Z = 0.53, P = 0.59). Gabapentin was similar to other neuromodulators in therapeutic efficacy (RR = 1.07,95%CI [0.87,1.32], Z = 0.64, P = 0.52), but its safety was better.
Gabapentin is effective in the treatment of chronic refractory cough in both subjective and objective evaluations, and its safety is better than other neuromodulators.

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: Supported by GlaxoSmithKline. J.A.S. was funded by an MRC Clinician Scientist award (G0701918).

: Disclosure of potential conflict of interest: R. Murdoch and A. Newlands are employed by and have stock holdings in GlaxoSmithKline. A. Woodcock has received research support from GlaxoSmithKline, Afferent, and Verona; has received consultancy fees from Merck; and has a patent on ambulatory cough monitor owned by University Hospital of South Manchester. J. A. Smith has received research support from GlaxoSmithKline, AstraZeneca, and Afferent; has received consulting fees from Almirall, GlaxoSmithKline, Xention, Glenmark, Theravance, Novartis, and Reckitt and Benckiser; and has a patent owned by the University Hospital South Manchester for describing methods for detecting cough from sound. The rest of the authors declare they have no relevant conflicts of interest.

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Asthma and lower airway diseaseTransient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: A double-blind randomized controlled trial

Background

Objective

Methods

Results

Conclusion

Section snippets

Methods

Subjects

Discussion

Pulm Pharmacol Ther

Chest

Neuroscience

Neuron

Pain

Bioorg Med Chem Lett

Pain

Chest

Gastroenterology

Pulm Pharmacol Ther

Pain

Respir Med

Respir Med

Lancet

Chest

Otolaryngol Clin North Am

Cough induced by stimulation of capsaicin-sensitive sensory neurons in conscious guinea-pigs

Acta Physiol Scand

Effects of aerosol-applied capsaicin, histamine and prostaglandin E2 on airway sensory receptors of anaesthetized cats

J Physiol

Effect of inhaled and systemic opiates on responses to inhaled capsaicin in humans

J Appl Physiol

Sensitivity of the cough reflex in patients with chronic cough

Eur Respir J

The utility of the mannitol challenge in the assessment of chronic cough: a pilot study

Cough

Cough reflex sensitivity and airway inflammation in patients with chronic cough due to non-acid gastro-oesophageal reflux

Respirology

Capsaicin cough sensitivity decreases with successful treatment of chronic cough

Am J Respir Crit Care Med

ERS guidelines on the assessment of cough

Eur Respir J

The capsaicin receptor: a heat-activated ion channel in the pain pathway

Nature

Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human

Proc Natl Acad Sci U S A

Transient receptor potential channels mediate the tussive response to prostaglandin E2 and bradykinin

Thorax

Asthma and lower airway disease
Transient receptor potential vanilloid 1 (TRPV1) antagonism in patients with refractory chronic cough: A double-blind randomized controlled trial