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Irwin RS, Madison JM. Unexplained or Refractory Chronic Cough in Adults. N Engl J Med 2025; 392:1203-1214. [PMID: 40138554 DOI: 10.1056/nejmra2309906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Affiliation(s)
- Richard S Irwin
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Massachusetts Chan Medical School, Worcester
| | - J Mark Madison
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Massachusetts Chan Medical School, Worcester
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2
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Lilly GL, Carroll T, Pietsch K, Dhillon V, Bryson PC, Akst LM. Refractory Chronic Cough: A State-of-the-Art Review for Otolaryngologists. Otolaryngol Head Neck Surg 2025; 172:419-435. [PMID: 39575647 DOI: 10.1002/ohn.1019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/31/2024] [Accepted: 09/21/2024] [Indexed: 01/29/2025]
Abstract
OBJECTIVE Patients with refractory chronic cough (RCC) are being seen in increasing numbers within otolaryngology clinics. Identifying the next steps in the evaluation and management of cough in patients who have had first-line treatment for gastroesophageal reflux, sinonasal disease, pulmonary disease, and angiotensin-converting enzyme inhibitor-related cough is paramount. This state-of-the-art review focuses on emerging treatments for RCC from an otolaryngology perspective. DATA SOURCES Pubmed. REVIEW METHODS The available literature on chronic cough, with a focus on RCC, emerging paradigms concerning pathophysiology, and evolving treatment approaches was reviewed and summarized. CONCLUSIONS Guided by a more detailed understanding of refractory cough physiology, a myriad of new treatment options have been developed to treat RCC. These are primarily aimed at disrupting what is thought to be a hypersensitive cough reflex, whether by a dampening of its sensory inputs or an alteration in motor activity, and are inclusive of neuromodulator treatments, superior laryngeal nerve blockade, vocal fold augmentation, botulinum toxin injection, topical capsaicin, and potentially the eventual use of P2X3 antagonists. Improved laryngopharyngeal reflux diagnosis and management, as well as the potential benefit of behavioral cough suppression therapy, are also discussed. IMPLICATIONS FOR PRACTICE The literature supporting each of these strategies is growing-and as more patients with RCC seek otolaryngology care, knowledge of these various approaches may improve the overall treatment of this condition.
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Affiliation(s)
- Gabriela L Lilly
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Thomas Carroll
- Department of Otolaryngology-Head and Neck Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kristine Pietsch
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Vaninder Dhillon
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Paul C Bryson
- Department of Otolaryngology, Cleveland Clinic Foundation, Boston, Massachusetts, USA
| | - Lee M Akst
- Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Abstract
In recent years, there has been a substantial increase in the development of antitussive therapies and the first new therapy, gefapixant has been licenced in Europe. This review describes current unlicenced treatments for chronic cough and details treatments currently in development for refractory chronic cough and cough in idiopathic pulmonary fibrosis, as well as compounds previously explored.
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Affiliation(s)
- Jaclyn A Smith
- Division of Immunology, Immunity to Infection and Respiratory Medicine, University of Manchester and Manchester Academic Health Science Centre, Wythenshawe Hospital, Southmoor Road, Manchester, M23 9LT, UK.
- Manchester University NHS Foundation Trust, Manchester, UK.
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Wright ML, Slovarp L, Reynolds J, Roy N, Okifuji A, Sundar KM, Barkmeier-Kraemer JM. Prevalence of Anxiety as a Variable in Treatment Outcomes for Individuals With Chronic Refractory Cough. AMERICAN JOURNAL OF SPEECH-LANGUAGE PATHOLOGY 2024; 33:476-484. [PMID: 38052060 DOI: 10.1044/2023_ajslp-23-00104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/07/2023]
Abstract
PURPOSE Anxiety is a mental state characterized by an intense sense of tension, worry, or apprehension relative to something adverse that might happen in the future. Anxiety is a known comorbidity in cough patients, yet its prevalence among those with chronic refractory cough (CRC) is unknown. Anxiety is not typically assessed during evaluation for CRC, but treatments for CRC such as neuromodulators and behavioral cough suppression therapy (BCST) may potentially attenuate anxiety. This preliminary study investigates the potential prevalence of anxiety in CRC and its possible role in treatment outcomes. METHOD CRC patients seen in a specialty clinic at the University of Utah or the University of Montana completed the Leicester Cough Questionnaire (LCQ) pre- and post-BCST treatment. Participants were dichotomized into positive anxiety screen (PAS) and negative anxiety screen (NAS) groups based on presence or absence of documented anxiety within electronic medical records at the University of Utah and based on a Generalized Anxiety Disorder-7 score > 5 at the University of Montana. RESULTS Of the 86 total participants, 37 (43%) were in the PAS group (29 females, Mage = 56 ± 13) and 49 (57%) were in the NAS group (36 females, Mage = 64 ± 14). Eighty-nine percent of CRC participants with a PAS reported a clinically meaningful improvement in LCQ total score following treatment compared to 65% of NAS participants. Furthermore, mean pre- to posttreatment change scores on the LCQ were significantly greater within the PAS group (p = .002, Cohen's d = 0.7, indicating a moderate to large effect size). CONCLUSION This preliminary study suggests that (a) anxiety may be prevalent among those with CRC and (b) those patients who screen positive for anxiety report greater benefit from BCST.
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Affiliation(s)
- Miranda L Wright
- Department of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City
- Department of Communication Sciences and Disorders, University of Utah, Salt Lake City
| | - Laurie Slovarp
- School of Speech, Language, Hearing and Occupation Sciences, University of Montana, Missoula
| | - Jane Reynolds
- School of Speech, Language, Hearing and Occupation Sciences, University of Montana, Missoula
| | - Nelson Roy
- Department of Communication Sciences and Disorders, University of Utah, Salt Lake City
| | - Akiko Okifuji
- Division of Pain Medicine, University of Utah, Salt Lake City
| | - Krishna M Sundar
- Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City
| | - Julie M Barkmeier-Kraemer
- Department of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City
- Department of Communication Sciences and Disorders, University of Utah, Salt Lake City
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Zhi H, Zhong M, Huang J, Zheng Z, Ji X, Xu Y, Dong J, Yan W, Chen Z, Zhan C, Chen R. Gabapentin alleviated the cough hypersensitivity and neurogenic inflammation in a guinea pig model with repeated intra-esophageal acid perfusion. Eur J Pharmacol 2023; 959:176078. [PMID: 37805133 DOI: 10.1016/j.ejphar.2023.176078] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 10/09/2023]
Abstract
OBJECTIVE The anti-tussive effect of gabapentin and its underlying neuromodulatory mechanism were investigated via a modified guinea pig model of gastroesophageal reflux-related cough (GERC). METHODS Intra-esophageal perfusion with hydrochloric acid (HCl) was performed every other day 12 times to establish the GERC model. High-dose gabapentin (48 mg/kg), low-dose gabapentin (8 mg/kg), or saline was orally administered for 2 weeks after modeling. Cough sensitivity, airway inflammation, lung and esophagus histology, levels of substance P (SP), and neurokinin-1 (NK1)-receptors were monitored. RESULTS Repeated intra-esophageal acid perfusion aggravated the cough sensitivity in guinea pigs in a time-dependent manner. The number of cough events was significantly increased after 12 times HCl perfusion, and the hypersensitivity period was maintained for 2 weeks. The SP levels in BALF, trachea, lung, distal esophagus, and vagal ganglia were increased in guinea pigs receiving HCl perfusion. The intensity of cough hypersensitivity in the GERC model was significantly correlated with increased SP expression in the airways. Both high and low doses of gabapentin administration could reduce cough hypersensitivity exposed to HCl perfusion, attenuate airway inflammatory damage, and inhibit neurogenic inflammation by reducing SP expression from the airway and vagal ganglia. CONCLUSIONS Gabapentin can desensitize the cough sensitivity in the GERC model of guinea pig. The anti-tussive effect is associated with the alleviated peripheral neurogenic inflammation as reflected in the decreased level of SP.
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Affiliation(s)
- Haopeng Zhi
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
| | - Mingyu Zhong
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
| | - Junfeng Huang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
| | - Ziwen Zheng
- Guangzhou Medical University, Guangzhou, Guangdong, 510180, China.
| | - Xiaolong Ji
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
| | - Yilin Xu
- Guangzhou Medical University, Guangzhou, Guangdong, 510180, China.
| | - Junguo Dong
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
| | - Wenbo Yan
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
| | - Zhe Chen
- Laboratory of Cough, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, Jiangsu, 215300, China.
| | - Chen Zhan
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
| | - Ruchong Chen
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, Guangdong, China.
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Yardstick for managing cough, part 1: In adults and adolescent patients older than 14 years of age. Ann Allergy Asthma Immunol 2023; 130:379-391. [PMID: 36526233 DOI: 10.1016/j.anai.2022.12.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022]
Abstract
Nationwide statistics in the United States and Australia reveal that cough of undifferentiated duration is the most common complaint for which patients of all ages seek medical care in the ambulatory setting. Management of chronic cough is one of the most common reasons for new patient visits to pulmonologists. Because symptomatic cough is such a common problem and so much has been learned about how to diagnose and treat cough of all durations but especially chronic cough, this 2-part yardstick has been written to review in a practical way the latest evidence-based guidelines most of which have been developed from recent high quality systematic reviews on how best to manage cough of all durations in adults, adolescents, and children. In this manuscript, part 1 of the 2-part series, we provide evidence-based, and expert opinion recommendations on the management of chronic cough in adult and adolescent patients (>14 years of age).
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Wu J, Ma Y, Chen Y. GERD-related chronic cough: Possible mechanism, diagnosis and treatment. Front Physiol 2022; 13:1005404. [PMID: 36338479 PMCID: PMC9630749 DOI: 10.3389/fphys.2022.1005404] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 10/07/2022] [Indexed: 11/04/2023] Open
Abstract
GERD, or gastroesophageal reflux disease, is a prevalent medical condition that affects millions of individuals throughout the world. Chronic cough is often caused by GERD, and chronic cough caused by GER is defined as GERD-related chronic cough (GERC). It is still unclear what the underlying molecular mechanism behind GERC is. Reflux theory, reflex theory, airway allergies, and the novel mechanism of esophageal motility disorders are all assumed to be linked to GERC. Multichannel intraluminal impedance combined with pH monitoring remains the gold standard for the diagnosis of GERC, but is not well tolerated by patients due to its invasive nature. Recent discoveries of new impedance markers and new techniques (mucosal impedance testing, salivary pepsin, real-time MRI and narrow band imaging) show promises in the diagnosis of GERD, but the role in GERC needs further investigation. Advances in pharmacological treatment include potassium-competitive acid blockers and neuromodulators (such as Baclofen and Gabapentin), prokinetics and herbal medicines, as well as non-pharmacological treatments (such as lifestyle changes and respiratory exercises). More options have been provided for the treatment of GERC other than acid suppression therapy and anti-reflux surgery. In this review, we attempt to review recent advances in GERC mechanism, diagnosis, and subsequent treatment options, so as to provide guidance for management of GERC.
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Affiliation(s)
| | - Yiming Ma
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yan Chen
- Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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8
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Chung KF, McGarvey L, Song WJ, Chang AB, Lai K, Canning BJ, Birring SS, Smith JA, Mazzone SB. Cough hypersensitivity and chronic cough. Nat Rev Dis Primers 2022; 8:45. [PMID: 35773287 PMCID: PMC9244241 DOI: 10.1038/s41572-022-00370-w] [Citation(s) in RCA: 129] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/19/2022] [Indexed: 12/13/2022]
Abstract
Chronic cough is globally prevalent across all age groups. This disorder is challenging to treat because many pulmonary and extrapulmonary conditions can present with chronic cough, and cough can also be present without any identifiable underlying cause or be refractory to therapies that improve associated conditions. Most patients with chronic cough have cough hypersensitivity, which is characterized by increased neural responsivity to a range of stimuli that affect the airways and lungs, and other tissues innervated by common nerve supplies. Cough hypersensitivity presents as excessive coughing often in response to relatively innocuous stimuli, causing significant psychophysical morbidity and affecting patients' quality of life. Understanding of the mechanisms that contribute to cough hypersensitivity and excessive coughing in different patient populations and across the lifespan is advancing and has contributed to the development of new therapies for chronic cough in adults. Owing to differences in the pathology, the organs involved and individual patient factors, treatment of chronic cough is progressing towards a personalized approach, and, in the future, novel ways to endotype patients with cough may prove valuable in management.
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Affiliation(s)
- Kian Fan Chung
- Experimental Studies Unit, National Heart & Lung Institute, Imperial College London, London, UK
- Department of Respiratory Medicine, Royal Brompton and Harefield Hospital, London, UK
| | - Lorcan McGarvey
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK
| | - Woo-Jung Song
- Department of Allergy and Clinical Immunology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Anne B Chang
- Australian Centre for Health Services Innovation, Queensland's University of Technology and Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, Queensland, Australia
- Division of Child Health, Menzies School of Health Research, Darwin, Northern Territory, Australia
| | - Kefang Lai
- The First Affiliated Hospital of Guangzhou Medical University, National Center of Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China
| | | | - Surinder S Birring
- Centre for Human & Applied Physiological Sciences, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Jaclyn A Smith
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, University of Manchester, Manchester, UK
| | - Stuart B Mazzone
- Department of Anatomy and Physiology, University of Melbourne, Victoria, Australia.
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9
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Ahmad SR, Iyer VN. The Evolving Clinical Practice of Chronic Cough. Mayo Clin Proc 2022; 97:1164-1175. [PMID: 35483988 DOI: 10.1016/j.mayocp.2022.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 12/13/2021] [Accepted: 02/09/2022] [Indexed: 11/24/2022]
Abstract
Chronic cough, defined as a cough lasting for greater than 8 weeks, accounts for a substantial number of primary care and specialist consultations in the United States. Although cough can arise from a myriad number of serious respiratory diseases, attention has traditionally focused on diagnosing and treating gastroesophageal reflux, upper airway cough syndrome, and eosinophilic airway inflammation (asthma and nonasthmatic eosinophilic bronchitis) in patients with normal chest imaging. The newly described paradigm and entity of cough hypersensitivity syndrome (CHS) becomes useful when the etiology of cough remains elusive or when the cough remains refractory despite appropriate therapy for underlying causes. We present an update on the evolving understanding of refractory chronic cough and/or unexplained chronic cough as manifestations of laryngeal hypersensitivity and CHS. This includes a focus on understanding the pathophysiology underlying current and novel therapeutics for CHS, while also ensuring that common causes of chronic cough continue to be evaluated and treated in a systematic multidisciplinary manner.
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Affiliation(s)
- Sumera R Ahmad
- Division of Pulmonary and Critical Care, Mayo Clinic, Rochester, MN, USA.
| | - Vivek N Iyer
- Division of Pulmonary and Critical Care, Mayo Clinic, Rochester, MN, USA
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Long-Term Treatment Outcomes after Behavioral Speech Therapy for Chronic Refractory Cough. Lung 2021; 199:517-525. [PMID: 34595607 DOI: 10.1007/s00408-021-00481-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/16/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Current literature reveals that up to 88% of individuals undergoing behavioral speech therapy (BST) for chronic refractory cough (CRC) demonstrate benefit at 4-8 weeks post-treatment. However, investigations of BST are confounded by overlapping use of neuromodulators, missing follow-up data, and an absence of long-term outcomes. This study investigated treatment outcomes beyond 6 months in individuals diagnosed with CRC, and whose treatment outcomes were clinically undocumented. METHODS Participants with CRC 6 months or greater beyond treatment completion were recruited. Participants completed a post-treatment Leicester Cough Questionnaire (LCQ) and a telephone interview. Demographic data, cough characteristics, treatment adherence, BST outcomes, and pre- and post-treatment LCQ scores were evaluated. RESULTS 80 individuals met inclusion criteria and 29 consented to participate. Of these, 27 were recommended BST. The majority were female (19/27) with average age of 58 years (SD = 12). Mean cough duration was 60 months (SD = 98) and mean post-BST duration was 20 months (SD = 9). A significant increase in pre- to post-treatment LCQ scores occurred [4.4 (SD = 4.2)] (p < 0.0001). CONCLUSION This study addressed long-term BST benefit for CRC and demonstrated a significant improvement in long-term post-treatment LCQ total scores more than a year after BST for CRC. More than half of participants indicated improvement or elimination of their cough. These findings further support the benefit of BST for CRC. Future research should consider patient perspectives about treatment outcomes given that 44% of participants reported no benefit from BST.
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11
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Effect of centrally and peripherally acting GABA B agonism on the healthy human cough reflex. Pulm Pharmacol Ther 2021; 71:102079. [PMID: 34571095 DOI: 10.1016/j.pupt.2021.102079] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 09/07/2021] [Accepted: 09/22/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND Currently there are no effective licensed anti-tussive therapies. Understanding how the neuronal mechanisms mediating the cough reflex in animal models translate to humans is important for the development of effective therapies. Pre-clinical studies suggest that the activation of GABAB receptors in both the peripheral and central nervous systems inhibit cough. OBJECTIVE To compare the effect of central and peripherally acting GABAB agonists (lesogaberan and baclofen) on the cough reflex in healthy volunteers. METHODS We performed a single center, double-blind, double-dummy, three-way crossover trial in healthy controls comparing single doses of lesogaberan (120 mg MR), with baclofen (40 mg) and placebos. Cough responses to inhaled capsaicin were assessed at screening and 2h post-dose on each study day. The primary endpoint was the maximum number of coughs evoked at any concentration of capsaicin (Emax) and the secondary endpoint was the concentration evoking 50% of the maximal response (ED50). RESULTS Fifteen participants enrolled onto the study (median age 29 (IQR 25-44) years; 7 females, mean BMI 24.6(±3.0). Lesogaberan treatment produced a small, statistically significant increase in Emax compared with placebo [mean 13.4coughs (95%CI 10.1-17.9) vs. 11.8coughs (8.8-15.9), p = 0.04], but had no effect on ED50 [geometric mean 47.4 μM (95%CI 24.4-91.7) vs 37.6 μM (95%CI 19.2-73.5), p = 0.37]. In contrast, baclofen had no significant effect on Emax (11.1, 95%CI 8.1-15.4) (p = 0.23), but significantly increased ED50 compared with placebo (geometric mean 75.2 μM (95%CI 37.2-151.8), p = 0.002). CONCLUSION This data suggests the anti-tussive actions of GABAB agonists, in healthy volunteers, occur in the central rather than the peripheral nervous system.
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12
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O’Hare C, Rahman T, Williams NT. Treatment of Chronic Refractory Cough in Adults: Focus on Neuromodulators and Other Therapeutic Modalities. J Pharm Technol 2020. [DOI: 10.1177/8755122520954866] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Objective: To evaluate the literature and educate health care professionals about the different management options for chronic refractory cough (CRC). Data Sources: Searches were performed through MEDLINE (1966 to July 2020) using OVID and EBSCOhost and EMBASE (1947 to July 2020) using OVID. Search terms included chronic cough, neurogenic cough, neuromodulators, chronic cough management, and chronic cough treatment. References of all relevant articles were further used to obtain additional articles. Study Selection and Data Extraction: This review includes articles in the English language and human trial literature. Twenty-three trials explored the use of oral neuromodulators in the management of CRC. Data Synthesis: CRC is a poorly understood disease that may have a complex neuropathic etiology. Oral neuromodulators, such as amitriptyline, baclofen, gabapentin, and pregabalin, continue to be the most commonly used agents for the management of CRC. Alternative pharmacological therapies such as botulinum toxin, anesthetic agents (benzonatate, lidocaine), and narcotic agents have efficacy data, and further research into effective doses and routes of administration is warranted. Alternative nonpharmacologic therapies more commonly used included speech pathology treatment. Conclusion: Several medication and alternative treatment interventions may be effective in managing CRC. Current studies used wide dosing and titration strategies, making it challenging to standardize therapy. No consistent method of assessing cough reflex was used between studies, as well as a lack of consistent randomization and small sample sizes. Additional research is needed to standardize treatment durations, optimum doses, and place in therapy of the available interventions in the management of CRC.
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Affiliation(s)
- Caroline O’Hare
- Southwestern Oklahoma State University, Weatherford, OK, USA
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Zhang M, Zhu Y, Dong R, Qiu Z. Gabapentin versus baclofen for treatment of refractory gastroesophageal reflux-induced chronic cough. J Thorac Dis 2020; 12:5243-5250. [PMID: 33145100 PMCID: PMC7578446 DOI: 10.21037/jtd-2020-icc-002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Refractory gastroesophageal reflux-induced chronic cough (GERC) is a special type of gastroesophageal reflux disease (GERD) with predominant cough resistant to pragmatic standard anti-reflux therapy including antisecretory agents alone or in combination with promotility agents but with a favorable response to intensified anti-reflux treatment. The condition is not rare and is difficult to treat. Neuromodulators such as baclofen and gabapentin are considered potential therapeutic options for refractory GERC. Limited data indicate that gabapentin and baclofen could attenuate the cough symptom in patients with refractory GERC by blockade of gastroesophageal reflux or by direct antitussive effects. However, no study has compared the efficacy of these two drugs in treatment of refractory GERC. In an open-labeled randomized clinical study, we demonstrated that, as add-on therapy, gabapentin and baclofen had a similar prevalence of therapeutic success for suspected refractory GERC but gabapentin may be more preferable because of its fewer central side effects. The efficacy of baclofen and gabapentin was suboptimal, so further studies are needed to select the patients with refractory GERC suitable for precise treatment using these two neuromodulators.
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Affiliation(s)
- Mengru Zhang
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yiqing Zhu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ran Dong
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhongmin Qiu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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Abstract
This article discusses vocal fold paresis as a separate and distinct condition from vocal fold paralysis. The signs and symptoms of paresis may be different and less obvious than those for paralysis, so this condition is often misdiagnosed or underdiagnosed. Elements necessary to heighten clinical suspicion are included to assist in educating practitioners on these subtle findings. Once paresis is suspected, associated respiratory or sensory abnormalities also should be sought, because these may change the treatment plan when recognized. Utility of laryngeal electromyography is discussed along with potential treatment options for both the motor and often-present sensory symptoms.
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Affiliation(s)
- Chandra M Ivey
- Icahn School of Medicine, Mount Sinai Hospital, New York, NY, USA.
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15
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Naik RD, Vaezi MF. Editorial: breaking the cycle of cough in GERD-neuromodulators to the rescue? Aliment Pharmacol Ther 2019; 49:1242-1243. [PMID: 30977175 DOI: 10.1111/apt.15205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Rishi D Naik
- Division of Gastroenterology, Hepatology, and Nutrition, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Michael F Vaezi
- Division of Gastroenterology, Hepatology, and Nutrition, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, Nashville, Tennessee
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Dong R, Xu X, Yu L, Ding H, Pan J, Yu Y, Shi C, Chen Q, Zhang M, Lv H, Qiu Z. Randomised clinical trial: gabapentin vs baclofen in the treatment of suspected refractory gastro-oesophageal reflux-induced chronic cough. Aliment Pharmacol Ther 2019; 49:714-722. [PMID: 30740748 DOI: 10.1111/apt.15169] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 01/06/2019] [Accepted: 01/11/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Neuromodulators are considered potential therapeutic options for refractory gastro-oesophageal reflux-induced chronic cough. AIM To compare the efficacy of gabapentin and baclofen in patients with suspected refractory gastro-oesophageal reflux-induced chronic cough. METHODS Two hundred and thirty-four patients with suspected refractory gastro-oesophageal reflux-induced chronic cough, who failed an 8-week course of omeprazole and domperidone, were recruited into the open-labelled study and randomly assigned to receive either gabapentin (maximum daily dose of 900 mg) or baclofen (maximum daily dose of 60 mg) for 8 weeks as add-on therapy to the previous treatment. The primary end point was the successful rate of cough resolution; and the secondary end-points included cough sensitivity to capsaicin and gastro-oesophageal reflux disease questionnaire score and reported side effects. RESULTS One hundred and eleven patients in the gabapentin group and 106 in the baclofen group completed the study. The overall success rate for cough resolution was comparable (57.3% vs 53.0%, χ2 = 0.357, P = 0.550) between the two groups. In parallel, cough sensitivity to capsaicin and gastro-oesophageal reflux disease questionnaire score decreased after treatment with either gabapentin or baclofen. However, gabapentin was associated with less frequent somnolence (20.5% vs 35.0%, χ2 = 6.156, P = 0.013) and dizziness (11.1% vs 23.9%, χ2 = 6.654, P = 0.010) than baclofen. CONCLUSIONS Gabapentin and baclofen have similar therapeutic efficacy for suspected refractory gastro-oesophageal reflux-induced chronic cough. However, gabapentin may be preferable because of fewer side effects. Trial Register: http://www.chictr.org/; No.: ChiCTR-ONC-13003066.
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Affiliation(s)
- Ran Dong
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xianghuai Xu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Li Yu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongmei Ding
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jing Pan
- Department of Respiratory Medicine, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yiming Yu
- Department of Respiratory Medicine, Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Cuiqin Shi
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiang Chen
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Mengru Zhang
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hanjing Lv
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhongmin Qiu
- Department of Pulmonary and Critical Care Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
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Simpson CB, Tibbetts KM, Loochtan MJ, Dominguez LM. Treatment of chronic neurogenic cough with in‐office superior laryngeal nerve block. Laryngoscope 2018; 128:1898-1903. [DOI: 10.1002/lary.27201] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 01/29/2018] [Accepted: 03/05/2018] [Indexed: 11/07/2022]
Affiliation(s)
- C. Blake Simpson
- Department of Otolaryngology–Head and Neck Surgery, University of Texas Voice CenterUniversity of Texas Health Science Center‐San Antonio San Antonio
| | - Kathleen M. Tibbetts
- Department of Otolaryngology–Head and Neck SurgeryUniversity of Texas Southwestern Medical CenterDallas Texas
| | | | - Laura M. Dominguez
- Department of Otolaryngology–Head and Neck Surgery, University of Texas Voice CenterUniversity of Texas Health Science Center‐San Antonio San Antonio
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18
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Wei W, Liu R, ZhangTong Y, Qiu Z. The efficacy of specific neuromodulators on human refractory chronic cough: a systematic review and meta-analysis. J Thorac Dis 2016; 8:2942-2951. [PMID: 27867572 DOI: 10.21037/jtd.2016.10.51] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND There have been several published reports on the use of orally administered, specific centrally acting medicines for the treatment of idiopathic cough; however, there is no extant systematic review of randomized controlled trials (RCTs) that evaluated their efficacy and safety for the treatment of idiopathic cough in human beings. METHODS We conducted a series of definitive systematic reviews and meta-analyses of RCTs. Claims data from the MEDLINE, EMBASE, LILACS, CBM, CNKI, VIP, Wan Fang, and Cochrane Library databases were used. We also reviewed articles and reference lists of relevant articles pertaining to human subjects published prior to March 26, 2016. No language restrictions were imposed. Two authors independently reviewed the titles and abstracts of the retrieved studies, which were matched using Review Manager 5.3 software. Disagreements were resolved by consensus. The outcome data were the number of subjects whose symptoms declined, measured by cough or Leicester Cough Questionnaire (LCQ) score. Random effect meta-analyses were used to pool the findings. Publication bias was assessed using funnel plots. RESULTS Three RCTs, regarding the medicines baclofen, amitriptyline, and gabapentin, were conducted involving 92 persons in total. Our reviews confirmed that baclofen, amitriptyline, and gabapentin show promise in the treatment of cough for select cases of refractory chronic cough. After-treatment relief of cough symptoms was significant (risk ratio =2.41; 95% CI: 1.15-5.04, n=84). Each of the medicines was well tolerated with minimal side effects. Methodological biases in the design and execution of cluster randomized trials might contribute to any selection bias in this review. CONCLUSIONS Baclofen, amitriptyline, and gabapentin may be effective 'non-specific' antitussives in clinical settings, although none of them are used in medical assessments or routinely included in the anatomic diagnostic protocol.
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Affiliation(s)
- Weili Wei
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Ruilin Liu
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Yangzi ZhangTong
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Zhongmin Qiu
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
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19
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20
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Xu X, Yu L, Chen Q, Lv H, Qiu Z. Diagnosis and treatment of patients with nonacid gastroesophageal reflux-induced chronic cough. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2016; 20:885-92. [PMID: 26759577 PMCID: PMC4696375 DOI: 10.4103/1735-1995.170625] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Gastroesophageal reflux (GER) is one of the most common causes of chronic cough, and chronic cough due to GER represents a subtype of GER-related diseases. Gastroesophageal reflux-induced chronic cough (GERC) can be divided into two subgroups based on the pH of the GER. Nonacid GERC is less common than acid GERC, and its diagnosis and treatment strategy have not been standardized. However, nonacid GERC usually presents with its unique set of characteristics and features upon diagnosis and treatment in the clinic. Although the underlying molecular mechanism of nonacid GERC is not fully understood, it is considered to be associated with reflux theory, reflex theory and airway hypersensitivity. Multi-channel intraluminal impedance combined with pH monitoring is a promising new technique that can detect both acid and nonacid reflux, and our findings as well as those of others have shown its usefulness in diagnosing nonacid GERC. Development of new diagnostic techniques has led to an increased rate of nonacid GERC diagnosis. We summarize our experience in the diagnosis and treatment of nonacid GERC and provide a guide for future therapeutic approaches.
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Affiliation(s)
- Xianghuai Xu
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Li Yu
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Qiang Chen
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Hanjing Lv
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Zhongmin Qiu
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
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21
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Refractory chronic cough due to gastroesophageal reflux: Definition, mechanism and management. World J Methodol 2015; 5:149-56. [PMID: 26413488 PMCID: PMC4572028 DOI: 10.5662/wjm.v5.i3.149] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 07/06/2015] [Accepted: 07/11/2015] [Indexed: 02/06/2023] Open
Abstract
Refractory chronic cough due to gastroesophageal reflux is a troublesome condition unresponsive to the standard medical anti-reflux therapy. Its underlying mechanisms may include incomplete acid suppression, non-acid reflux, transient lower esophageal sphincter relaxations and esophageal hypersensitivity. The diagnosis of this disorder depends on both the findings of multi-channel intraluminal impedance-pH monitoring and the subsequent intensified anti-reflux therapy. The strategies of pharmacological treatment for refractory chronic cough due to reflux include the optimization of proton pump inhibitors and add-on therapies with histamine H2 receptor antagonists, baclofen and gabapentin. However, the further study is needed to satisfy its management.
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22
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Mazzone SB, McGovern AE, Farrell MJ. Endogenous central suppressive mechanisms regulating cough as potential targets for novel antitussive therapies. Curr Opin Pharmacol 2015; 22:1-8. [PMID: 25704497 DOI: 10.1016/j.coph.2015.02.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 02/04/2015] [Accepted: 02/04/2015] [Indexed: 02/05/2023]
Abstract
Cough and the accompanying sensation known as the urge-to-cough are complex neurobiological phenomena dependent on sensory and motor neural processing at many levels of the neuraxis. In addition to the excitatory neural circuits that provide the positive drive for inducing cough and the urge-to-cough, recent studies have highlighted the existence of likely inhibitory central neural processes that can be engaged to suppress cough sensorimotor processing. In many respects, the balance between excitatory and inhibitory central cough control may be a critical determinant of cough in health and disease which argues for the importance of understanding the biology of these putative central inhibitory processes. This brief review summarises the current knowledge of the central circuits that govern voluntary and involuntary cough suppression and posits the notion of targeting central suppressive mechanisms as a treatment for disordered cough in disease.
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Affiliation(s)
- Stuart B Mazzone
- School of Biomedical Sciences, The University of Queensland, Australia.
| | - Alice E McGovern
- School of Biomedical Sciences, The University of Queensland, Australia
| | - Michael J Farrell
- Department of Medical Imaging and Radiation Sciences, Monash University, Australia
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23
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Altman KW, Noordzij JP, Rosen CA, Cohen S, Sulica L. Neurogenic cough. Laryngoscope 2015; 125:1675-81. [DOI: 10.1002/lary.25186] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 12/01/2014] [Accepted: 01/08/2015] [Indexed: 01/22/2023]
Affiliation(s)
- Kenneth W. Altman
- Department of Otolaryngology-Head & Neck Surgery; Baylor College of Medicine; Houston Texas
| | - J. Pieter Noordzij
- Department of Otolaryngology-Head & Neck Surgery; Boston University Medical Center; Boston Massachusetts
| | - Clark A. Rosen
- Department of Otolaryngology; University of Pittsburgh School of Medicine; Pittsburgh Pennsylvania
| | - Seth Cohen
- Division of Otolaryngology-Head & Neck Surgery; Duke University Medical Center; Durham North Carolina
| | - Lucian Sulica
- Department of Otolaryngology-Head & Neck Surgery; Weill Cornell Medical College; New York New York
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24
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Dicpinigaitis PV, Morice AH, Birring SS, McGarvey L, Smith JA, Canning BJ, Page CP. Antitussive drugs--past, present, and future. Pharmacol Rev 2014; 66:468-512. [PMID: 24671376 PMCID: PMC11060423 DOI: 10.1124/pr.111.005116] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Cough remains a serious unmet clinical problem, both as a symptom of a range of other conditions such as asthma, chronic obstructive pulmonary disease, gastroesophageal reflux, and as a problem in its own right in patients with chronic cough of unknown origin. This article reviews our current understanding of the pathogenesis of cough and the hypertussive state characterizing a number of diseases as well as reviewing the evidence for the different classes of antitussive drug currently in clinical use. For completeness, the review also discusses a number of major drug classes often clinically used to treat cough but that are not generally classified as antitussive drugs. We also reviewed a number of drug classes in various stages of development as antitussive drugs. Perhaps surprising for drugs used to treat such a common symptom, there is a paucity of well-controlled clinical studies documenting evidence for the use of many of the drug classes in use today, particularly those available over the counter. Nonetheless, there has been a considerable increase in our understanding of the cough reflex over the last decade that has led to a number of promising new targets for antitussive drugs being identified and thus giving some hope of new drugs being available in the not too distant future for the treatment of this often debilitating symptom.
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Affiliation(s)
- P V Dicpinigaitis
- King's College London, Franklin Wilkins Building, 100 Stamford St., London, SE1 9NH, UK.
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Xu XH, Yang ZM, Chen Q, Yu L, Liang SW, Lv HJ, Qiu ZM. Therapeutic efficacy of baclofen in refractory gastroesophageal reflux-induced chronic cough. World J Gastroenterol 2013; 19:4386-4392. [PMID: 23885151 PMCID: PMC3718908 DOI: 10.3748/wjg.v19.i27.4386] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Revised: 05/03/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy and safety of baclofen for treatment of refractory gastroesophageal reflux-induced chronic cough (GERC) unresponsive to standard anti-reflux therapy.
METHODS: Sixteen patients with refractory GERC were given an 8-wk course of baclofen 20 mg three times a day as an add-on therapy to omeprazole. Changes in the cough symptom score, cough threshold to capsaicin, reflux symptom score and possible adverse effects were determined after treatment. The variables of multi-channel intraluminal impedance combined with pH monitoring were compared between responders and non-responders to baclofen.
RESULTS: Twelve of 16 patients completed treatment. Cough disappeared or improved in 56.3% (9/16) of patients, including 6 patients with acid reflux-induced cough (66.7%) and 3 patients with non-acid reflux-induced cough (33.3%). With baclofen treatment, the cough symptom score began to decrease at week 2, was clearly decreased at week 6 and reached a minimum at week 8. At the end of therapy, the lowest concentration of capsaicin required for induction of ≥ 2 and ≥ 5 coughs increased from 0.98 (1.46) to 1.95 (6.82) μmol/L (Z = -2.281, P = 0.024) and from 1.95 (7.31) to 7.8 (13.65) μmol/L (Z = -2.433, P = 0.014), respectively, and the reflux symptom score decreased from 8.0 ± 1.6 to 6.8 ± 0.8 (t = 2.454, P = 0.023). The number of acid reflux episodes was significantly lower in responders than in non-responders. The main adverse effects were somnolence, dizziness and fatigue.
CONCLUSION: Baclofen is a useful, but suboptimal treatment option for refractory GERC.
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26
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Castillo D, Pitts T. Influence of baclofen on laryngeal and spinal motor drive during cough in the anesthetized cat. Laryngoscope 2013; 123:3088-92. [PMID: 23670824 DOI: 10.1002/lary.24143] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Revised: 03/18/2013] [Accepted: 03/18/2013] [Indexed: 11/07/2022]
Abstract
OBJECTIVES/HYPOTHESIS The antitussive properties of (±) baclofen on laryngeal muscle activities have not been determined. The hypothesis of this study was that administration of (±) baclofen would suppress upper airway muscle motor activity in a dose-dependent manner during cough. STUDY DESIGN This is a prospective, preclinical, hypothesis-driven, paired design. METHODS Electromyograms of the parasternal, rectus abdominis, thyroarytenoid, posterior cricoarytenoid, and thyrohyoid were measured, along with esophageal pressure. Cough was elicited by mechanical stimulation of the lumen of the intrathoracic trachea in spontaneously breathing cats. RESULTS Baclofen (±) (3-10 μg kg(-1) i.a.) induced decreases in the electromyogram amplitude of the rectus abdominis motor drive during coughing, the inspiratory and active expiratory (E1) phases of cough, and cough number per epoch. There was no effect of (±) baclofen on the EMG amplitudes of any of the laryngeal muscles, the parasternal, or the duration of the passive expiratory (E2) phase. CONCLUSIONS Results from the present study indicate differential control mechanisms for laryngeal and inspiratory motor drive during cough, providing evidence of a control system regulating laryngeal activity and inspiratory spinal drive that is divergent from the control of expiratory spinal motoneurons.
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Affiliation(s)
- Daniel Castillo
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, U.S.A
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27
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Smith JA, Houghton LA. The oesophagus and cough: laryngo-pharyngeal reflux, microaspiration and vagal reflexes. COUGH 2013; 9:12. [PMID: 23590893 PMCID: PMC3640905 DOI: 10.1186/1745-9974-9-12] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 03/17/2013] [Indexed: 12/25/2022]
Abstract
Gastro-oesophageal reflux disease is generally considered to be one of the commonest causes of chronic cough, however randomised controlled trials of proton pump inhibitors have often failed to support this notion. This article reviews the most recent studies investigating the mechanisms thought to link reflux and cough, namely laryngo-pharyngeal reflux, micro-aspiration and neuronal cross-organ sensitisation. How recent evidence might shed light on the failure of acid suppressing therapies and suggest new approaches to treating reflux related cough are also discussed.
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Affiliation(s)
- Jaclyn A Smith
- Respiratory and Allergy Centre, The University of Manchester, University Hospital of South Manchester, Manchester, UK.
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28
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Cohen SM, Misono S. Use of specific neuromodulators in the treatment of chronic, idiopathic cough: a systematic review. Otolaryngol Head Neck Surg 2013; 148:374-82. [PMID: 23300226 PMCID: PMC5813813 DOI: 10.1177/0194599812471817] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Accepted: 11/29/2012] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The goal of this systematic review was to examine the evidence for the use of the neuromodulating agents, amitriptyline, gabapentin, pregabalin, and baclofen, in the management of chronic, idiopathic cough patients. DATA SOURCES Online databases, including PubMed, Embase, Cochrane Review, and Web of Science, and publications cited in bibliographies were used. REVIEW METHODS Literature was searched by the 2 authors with a priori criteria for study selection. RESULTS Eight relevant articles were identified, including 2 randomized controlled trials, 2 prospective cohort or case-series designs with consecutive patients, 1 retrospective case series of consecutive patients, 1 retrospective case series whose consecutive status was not known, and 2 case reports of 6 and 2 patients, respectively. Improvements in cough-specific quality of life were noted in the randomized controlled trials. Cough severity was reduced in studies that measured this outcome measure. In the remaining studies, cough symptoms were less after neuromodulator treatment. CONCLUSION Benefit from neuromodulator treatment with amitriptyline, gabapentin, pregabalin, and baclofen in chronic, idiopathic cough patients was demonstrated. Further investigations using objective and subjective outcome measures are needed as well as studies exploring optimal dose, length of treatment, and relapse rates posttreatment.
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Affiliation(s)
- Seth M Cohen
- Duke Voice Care Center, Division of Otolaryngology-Head & Neck Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
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29
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Novel antitussive strategies. Drug Discov Today 2012; 18:380-8. [PMID: 23159360 DOI: 10.1016/j.drudis.2012.11.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2012] [Revised: 10/17/2012] [Accepted: 11/08/2012] [Indexed: 01/25/2023]
Abstract
Acute and chronic cough represent one of the most common symptoms of medical importance but effective pharmacotherapy is, to all intents and purposes, absent. Numerous initiatives targeting the recently discovered tussive pathways are in progress. Here, we review the current antitussive armamentarium and provide an update on the novel strategies and compounds in development.
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30
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Xu X, Chen Q, Liang S, Lü H, Qiu Z. Successful resolution of refractory chronic cough induced by gastroesophageal reflux with treatment of baclofen. COUGH 2012; 8:8. [PMID: 23078809 PMCID: PMC3500706 DOI: 10.1186/1745-9974-8-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2012] [Accepted: 10/01/2012] [Indexed: 12/18/2022]
Abstract
Gastroesophageal reflux induced cough is a common cause of chronic cough, and proton pump inhibitors are a standard therapy. However, the patients unresponsive to the standard therapy are difficult to treat and remain a challenge to doctors. Here, we summarized the experience of successful resolution of refractory chronic cough due to gastroesophageal reflux with baclofen in three patients. It is concluded that baclofen may be a viable option for gastroesophageal reflux induced cough unresponsive to proton pump inhibitor therapy.
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Affiliation(s)
- Xianghuai Xu
- Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, No, 389 Xincun Road, Shanghai, 200065, China.
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31
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Pharmacologic therapy for cough. Curr Opin Pharmacol 2011; 11:224-30. [PMID: 21724464 DOI: 10.1016/j.coph.2011.06.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Revised: 05/25/2011] [Accepted: 06/06/2011] [Indexed: 01/28/2023]
Abstract
Cough is the commonest symptom for which patients seek medical care and yet effective, well-tolerated cough medicines remain a significant unmet clinical need. The development of anti-tussive agents has probably been restricted by a number of factors; our understanding of the specific mechanisms evoking cough in different diseases and how this differs from the role of cough as a protective reflex is limited. Also well-validated tools for the assessment of cough have been lacking. These issues have not encouraged investment by the pharmaceutical industry and there have been no new licensed treatments for cough in more than 50 years. This article will use a mechanism-based approach to discuss the clinical evidence for the anti-tussive activity of currently available agents.
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32
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Froestl W. Chemistry and Pharmacology of GABAB Receptor Ligands. GABABRECEPTOR PHARMACOLOGY - A TRIBUTE TO NORMAN BOWERY 2010; 58:19-62. [DOI: 10.1016/s1054-3589(10)58002-5] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Agostinis P, Bardus P, Di Piazza V, Dassi F, Durigon N, Englaro A, Grillo P, Marchetti E, Petris T, Sabatini E. Terapia della tosse refrattaria con baclofene. ITALIAN JOURNAL OF MEDICINE 2009. [DOI: 10.1016/j.itjm.2009.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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34
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Dicpinigaitis PV. Currently available antitussives. Pulm Pharmacol Ther 2009; 22:148-51. [DOI: 10.1016/j.pupt.2008.08.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2008] [Accepted: 08/09/2008] [Indexed: 02/08/2023]
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35
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Li HL, Kang YM, Yu L, Xu HY, Zhao H. MELATONIN REDUCES BLOOD PRESSURE IN RATS WITH STRESS-INDUCED HYPERTENSION VIA GABAARECEPTORS. Clin Exp Pharmacol Physiol 2009; 36:436-40. [DOI: 10.1111/j.1440-1681.2008.05080.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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36
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Chung KF, Widdicombe J. Peripheral mechanisms II: the pharmacology of peripherally active antitussive drugs. Handb Exp Pharmacol 2009; 187:155-86. [PMID: 18825340 PMCID: PMC7122788 DOI: 10.1007/978-3-540-79842-2_8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Cough is an indispensable defensive reflex. Although generally beneficial, it is also a common symptom of diseases such as asthma, chronic obstructive pulmonary disease, upper respiratory tract infections, idiopathic pulmonary fibrosis and lung cancer. Cough remains a major unmet medical need and although the centrally acting opioids have remained the antitussive of choice for decades, they have many unwanted side effects. However, new research into the behaviour of airway sensory nerves has provided greater insight into the mechanisms of cough and new avenues for the discovery of novel non-opioid antitussive drugs. In this review, the pathophysiological mechanisms of cough and the development of novel antitussive drugs are reviewed.
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Affiliation(s)
- Kian Fan Chung
- National Heart & Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY UK
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Chung KF. Clinical cough VI: the need for new therapies for cough: disease-specific and symptom-related antitussives. Handb Exp Pharmacol 2009:343-368. [PMID: 18825350 DOI: 10.1007/978-3-540-79842-2_18] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
Cough is a common symptom that can be self-limiting or persistent. Ideally, treatment of the underlying cause(s) of cough with specific treatments should eliminate cough. This approach may not be successful if no cause can be established or if the treatment of the cause fails. Suppression of cough may be disease-specific or symptom-related. There has been a long tradition in acute cough usually due to upper respiratory tract infections to use symptom-related antitussives. In chronic cough, suppression of cough may be achieved by disease-specific therapies, but in many patients it may be necessary to use symptomatic antitussives. The efficacy of some over-the-counter symptomatic antitussives is often no better than that of a placebo. Currently available cough suppressants include the centrally acting opioids such as morphine, codeine, pholcodeine, and dextromethorphan. Early studies reported success in reducing cough in patients with chronic bronchitis or chronic obstructive pulmonary disease (COPD); however, a carefully conducted blinded controlled study showed no effect of codeine on cough of COPD. Success with these cough suppressants may be achieved at high doses that are associated with side effects. A slow-release preparation of morphine has been shown to have some degree of efficacy, but this should be reserved for the most severe chronic cough patient, and for patients with terminal cancer who may also benefit from its analgesic effects. There are case reports of the success of centrally acting drugs such as amitriptyline, paroxetine, gabapentin, and carbamezepine in chronic cough. New agents derived from basic research such as new opioids such as nociceptin or antagonists of transient receptor potential vanniloid-1 may turn out to have antitussive effects. Efficacy of symptomatic cough suppressants must be tested in double-blind randomized trials using validated measures of cough in patients with chronic cough not responding to specific treatments. Patients with chronic cough need effective antitussives that could be used either on demand or on a long-term basis.
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Affiliation(s)
- K F Chung
- National Heart and Lung Institute, Imperial College London, London, UK.
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Clinical cough II: therapeutic treatments and management of chronic cough. Handb Exp Pharmacol 2008:277-95. [PMID: 18825346 DOI: 10.1007/978-3-540-79842-2_14] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Chronic cough is a common and frequently disruptive symptom which can be difficult to treat with currently available medicines. Asthma/eosinophilic airway disease and gastro-oesophageal reflux disease are most commonly associated with chronic cough but it may also trouble patients with chronic obstructive pulmonary disease, pulmonary fibrosis and lung cancer. Over the last three decades there have been a number of key advances in the clinical approach to cough and a number of international guidelines on the management of cough have been developed. Despite the undoubted benefit of such initiatives, more effective treatments for cough are urgently needed. The precise pathophysiological mechanisms of chronic cough are unknown but central to the process is sensitization (upregulation) of the cough reflex. One well-recognized clinical consequence of this hypersensitive state is bouts of coughing triggered by apparently trivial provocation such as scents and odours and changes in air temperature. The main objective of new treatments for cough would be to identify ways to downregulate this heightened cough reflex but yet preserve its crucial role in protecting the airway. The combined efforts of clinicians, scientists and the pharmaceutical industry offer most hope for such a treatment breakthrough. The aim of this chapter is to provide some rationale for the current treatment recommendations and to offer some reflections on the management of patients with chronic cough.
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Estfan B, Walsh D. The cough from hell: diazepam for intractable cough in a patient with renal cell carcinoma. J Pain Symptom Manage 2008; 36:553-8. [PMID: 18440768 DOI: 10.1016/j.jpainsymman.2007.12.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2007] [Revised: 10/28/2007] [Accepted: 12/10/2007] [Indexed: 10/22/2022]
Abstract
Cough is a common symptom in cancer. Its underlying cause should be managed when identified; otherwise, empiric treatment is the mainstay of symptom control. Cancer-related cough usually responds to radiation therapy, an opioid, or benzonatate, a peripheral anesthetic. We present the case of a patient with renal cell carcinoma hospitalized for intractable cough that failed to respond adequately to usual treatments, but improved with diazepam.
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Affiliation(s)
- Bassam Estfan
- The Harry R Horvitz Center for Palliative Medicine, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
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Chung KF. Chronic cough: future directions in chronic cough: mechanisms and antitussives. Chron Respir Dis 2008; 4:159-65. [PMID: 17711916 DOI: 10.1177/1479972307077894] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Cough is an important defensive reflex of the respiratory tract needed to clear and protect the upper airways; however, it may become exaggerated and interfere with quality of life. Although chronic cough may be successfully treated when associated with the common causes such as asthma and eosinophilic bronchitis, gastrooesophageal reflux disease and post-nasal drip syndrome or rhinosinusitis, increasingly, idiopathic cough or cough with no associated cause is recognised. Chronic cough is often associated with an increased response to tussive agents such as capsaicin, used as an index of the cough reflex. Some airway receptors mediate or influence cough through activation of vagal afferent pathways which converge on brain stem respiratory networks and of supramedullary centres. Plastic changes in intrinsic and synaptic excitability at the brain stem, spinal or ganglionic level may be the mechanism by which the cough reflex is enhanced in chronic cough. Subjective and objective measurements of cough in the clinic are now available but a major unmet need in chronic cough is the availability of effective antitussives. Future directions in chronic cough include the pathophysiological mechanisms of the enhanced cough reflex, and the discovery of effective antitussives that can successfully alleviate chronic cough.
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Affiliation(s)
- K F Chung
- National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, UK.
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Chung KF. Currently Available Cough Suppressants for Chronic Cough. Lung 2007; 186 Suppl 1:S82-7. [PMID: 17909897 DOI: 10.1007/s00408-007-9030-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2007] [Accepted: 08/15/2007] [Indexed: 01/28/2023]
Abstract
Chronic cough is a common symptom but only a fraction of patients seek medical attention. Addressing the causes of chronic cough may lead to control of cough; however, this approach is not always successful since there is a certain degree of failure even when the cause(s) of cough are adequately treated; in idiopathic cough, there is no cause to treat. Persistent cough may be associated with deterioration of quality of life, and treatment with cough suppressants is indicated. Currently available cough suppressants include the centrally acting opioids such as morphine, codeine, and dextromethorphan. Peripherally acting antitussives include moguisteine and levodropropizine. Early studies report success in reducing cough in patients with chronic bronchitis or COPD; however, a carefully conducted study showed no effect of codeine on cough of COPD. Success with these cough suppressants can be achieved at high doses that are associated with side effects. Slow-release morphine has been reported to be useful in controlling intractable cough with good tolerance to constipation and drowsiness. There have been case reports of the success of centrally acting drugs such as amitryptiline, paroxetine, gabapentin, and carbamezepine in chronic cough. New opioids such as nociceptin or antagonists of TRPV1 may turn out to be more effective. Efficacy of cough suppressants must be tested in double-blind randomised trials using validated measures of cough in patients with chronic cough not responding to specific treatments. Patients with chronic cough are in desperate need of effective antitussives that can be used either on demand or on a long-term basis.
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Affiliation(s)
- Kian Fan Chung
- National Heart & Lung Institute, Imperial College London, and Royal Brompton & Harefield NHS Trust, London, UK.
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Chung KF. Effective antitussives for the cough patient: an unmet need. Pulm Pharmacol Ther 2006; 20:438-45. [PMID: 17161637 DOI: 10.1016/j.pupt.2006.10.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2006] [Accepted: 10/26/2006] [Indexed: 02/07/2023]
Abstract
Chronic cough is a prevalent symptom in the community but it is likely that only a small fraction of chronic coughers seek medical attention. Chronic cough can be controlled by addressing the 'cause' of the cough, but not all cough is controlled using this approach; an 'idiopathic' cough or cough of unknown aetiology is becoming more well-recognized. In these patients and in those whose cough has not responded to treatment of the cause(s), there is a lack of efficacious antitussive therapies ('non-specific' antitussives). Even in those whose cough is controlled by treatment of the cause, an efficacious antitussive for symptomatic relief would be useful for breakthrough symptoms. It is necessary to address the mechanisms underlying chronic cough, particularly the process of sensitization, both peripherally and centrally, that is the basis of chronic cough; such a process may persist even in the absence of the initiating event that first induced the cough. Currently-available antitussives in both acute and chronic cough are not very effective. Novel targets that may result in effective antitussives have been identified and with the development of clinical tools to measure cough accurately and reliably (e.g. cough counts and cough-specific quality-of-life questionnaires) and the evoked cough response (e.g. citric acid or capsaicin challenges), clinical trials should be performed. The chronic cough population is clinically heterogeneous but is characterized by an enhanced cough reflex; this should be the target population for study. Patients with chronic cough are in desperate need of effective antitussives that can be used either on demand or on a long-term basis.
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Affiliation(s)
- K F Chung
- National Heart and Lung Institute, Imperial College London and Royal Brompton and Harefield NHS Trust, London SW3, UK.
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Abstract
BACKGROUND Capsaicin, the pungent extract of red peppers, has achieved widespread use in clinical research because it induces cough in a dose-dependent and reproducible manner. Although > 2 decades of experience has led investigators to consider capsaicin cough challenge testing a safe diagnostic modality, this issue has not been specifically addressed in the literature. STUDY OBJECTIVES To review the published experience with capsaicin inhalation challenge testing in terms of safety. DESIGN Literature review and personal communication with study authors. SETTING Academic medical center. RESULTS One hundred twenty-two published studies since 1984 described 4,833 subjects (4,374 adults, 459 children) undergoing capsaicin cough challenge, with no serious adverse events reported. Subjects included healthy volunteers as well as patients with asthma, COPD, pathologic cough, and other respiratory conditions. Minor complaints described in a small fraction of studies consisted mainly of transient throat irritation. Personal communication with the authors of > 90% of the studies confirmed an absence of any serious adverse events. Furthermore, these investigators have performed thousands of additional capsaicin challenge studies not reported in the literature, also without any associated serious adverse events. CONCLUSIONS A review of the 20-year clinical experience has failed to uncover a single serious adverse event associated with capsaicin cough challenge testing in humans. Given the need for better antitussive therapies, capsaicin represents a vital component of future scientific inquiry in the field of cough.
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Affiliation(s)
- Peter V Dicpinigaitis
- Einstein Division/Montefiore Medical Center, Albert Einstein College of Medicine, 1825 Eastchester Road, Bronx, NY 10461, USA.
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Abstract
Cough is among the most common complaints for which patients seek medical attention. Consequently, enormous expenditures are made worldwide on prescription and non-prescription cough remedies. Multiple prospective studies have shown that specific antitussive therapy aimed at the underlying aetiology of cough is highly successful. The greatest current need therefore is for more effective nonspecific antitussive therapy, whose purpose is to suppress the cough reflex and provide symptomatic relief regardless of the underlying mechanism. Such therapy is particularly required for prolonged cough following upper respiratory tract infection, cough whose underlying aetiology is not easily treated, and idiopathic cough. Many areas of inquiry are currently ongoing that may lead to the development of novel and effective antitussive drugs.
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Affiliation(s)
- Peter V Dicpinigaitis
- Einstein Division/Montefiore Medical Center, Albert Einstein College of Medicine, Jack D Weiler Hospital, 1825 Eastchester Road, Bronx, NY 10461, USA.
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Dykewicz MS. Cough and angioedema from angiotensin-converting enzyme inhibitors: new insights into mechanisms and management. Curr Opin Allergy Clin Immunol 2004; 4:267-70. [PMID: 15238791 DOI: 10.1097/01.all.0000136759.43571.7f] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Angiotensin-converting enzyme inhibitors are widely prescribed for hypertension and heart failure. These drugs are commonly associated with cough, and are less commonly associated with angioedema, which may be potentially life threatening. This review describes data that extend our understanding of the mechanisms of these reactions, and provides guidance about clinical management. RECENT FINDINGS For patients who develop angioedema from angiotensin-converting enzyme inhibitors, recent data are reassuring that the majority of such patients can tolerate angiotensin-II receptor blockers. These data support earlier conclusions that most patients with angiotensin-converting enzyme inhibitor-induced cough can tolerate angiotensin-II receptor blockers. Limited case reports suggest that in acute angioedema induced by angiotensin-converting enzyme inhibitors, patients refractory to standard treatment may benefit from the infusion of fresh frozen plasma. SUMMARY Although data are incomplete, it appears that angiotensin-converting enzyme inhibitors cause cough and angioedema through a cascade of effects that begins with the accumulation of kinins, and then involves arachidonic acid metabolism and nitric oxide generation. Most patients who develop either cough or angioedema from angiotensin-converting enzyme inhibitors can tolerate angiotensin-II receptor blocking agents.
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Affiliation(s)
- Mark S Dykewicz
- Division of Allergy and Immunology, Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, Missouri 63104, USA.
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Abstract
Although the frequency of physician consultations and the sale of over-the-counter remedies establish the high prevalence of acute cough in the elderly, epidemiological studies have tended to be imprecise. However, respiratory tract infections in nose, larynx and/or bronchi, either viral or bacterial or both, are by far the commonest cause of acute cough. These are especially frequent and hazardous in the elderly, and community living and institutionalisation may aggravate this problem. A variety of viruses and bacteria have been incriminated, with rhinovirus, influenza and respiratory syncytial viruses, and Streptococcus pneumoniae, Haemophilus influenza and Bordetella pertussis being especially important. Viral infections can readily lead to community-acquired pneumonia. Successful diagnosis should point to successful treatment, and in this respect clinical examination and patient history are paramount, supplemented by chest X-ray, viral and bacterial culture and serological testing. Depending on the results of these tests, specific antibacterial therapy may be called for, although there is dispute as to the merits of antibacterial therapy in cases of uncertain diagnosis. Prevention and prophylaxis for influenza and S. pneumoniae infections are now commendably routine in the elderly, especially those in communities. Treatment, as well as the use of antibacterials, may also be directed against the inflammatory and infective processes in the airways. Non-specific antitussive therapy is common and usually highly desirable to prevent the adverse effects of repeated coughing. There have been few advances in antitussive therapy in recent years, opioids and dextromethorphan being the most commonly used agents; they act centrally on the brainstem, but also have a large placebo effect. However they work, they are much appreciated by patients and their partners. Moreover, striking advances in our understanding of the peripheral sensory and central nervous pathways of the cough reflex in recent years should soon lead to a new and more specific choice of agents to inhibit cough.
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Abstract
Chronic cough is a debilitating symptom for which patients commonly seek medical attention. Among adult non-smokers who are not taking an angiotensin-converting enzyme inhibitor and have a normal or near normal chest radiograph, postnasal drip syndrome caused by a variety of rhinosinus conditions, asthma and non-asthmatic eosinophilic bronchitis and gastro-oesophageal reflux disease singly or in combination, are the most common diagnoses underlying chronic cough. Pharmacotherapy for chronic cough can be either specific or non-specific. Specific therapy is preferable and the most effective as it is directed at the aetiologies and pathophysiological mechanisms responsible for cough. In contrast, non-specific therapy is used only in limited clinical settings, as it is directed at the symptom rather than underlying aetiologies and aims only to control, rather than eliminate cough.
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Affiliation(s)
- J Mark Madison
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA.
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Abstract
Treatment of chronic cough should always be etiologic. Recurrent viral infections are the most frequent problem. Utilisation of antitussive drugs must be limited, of short duration and without contraindications. Antitussive medications are classified in opiate and nonopiate, with central or peripheral action.
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Affiliation(s)
- V David
- Service de pédiatrie, hôpital Mère-Enfant, quai Moncousu, 44093 Nantes, France.
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Dicpinigaitis PV, Grimm DR, Lesser M. Baclofen-induced cough suppression in cervical spinal cord injury. Arch Phys Med Rehabil 2000; 81:921-3. [PMID: 10896005 DOI: 10.1053/apmr.2000.5612] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
OBJECTIVE To determine the effect of the GABA-agonist baclofen on cough reflex sensitivity in subjects with cervical spinal cord injury (C-SCI). Baclofen has been shown to inhibit the cough reflex in able-bodied volunteers. DESIGN Prospective, nonrandomized control trial. SETTING Veterans Affairs medical center with large outpatient SCI population. PARTICIPANTS Twelve adult males (11 outpatients) with C-SCI chronically maintained on oral baclofen for the treatment of muscle spasm. INTERVENTION Subjects underwent cough challenge testing with inhaled capsaicin. The concentrations (microM) of capsaicin inducing 2 or more (C2) and 5 or more (C5) coughs were determined. Mean values for log C2 and log C5 were compared with a control group of outpatients with C-SCI not receiving baclofen. RESULTS Subjects treated with baclofen had a significantly higher cough threshold (diminished cough reflex sensitivity) than control subjects. Mean (+/- standard error of the mean) values for log C2 in study subjects and controls were 1.28 +/- .16 and .65 +/- .15, respectively (p = .009). Mean values for log C5 in subjects receiving baclofen and in control subjects were 2.20 +/- .22 and 1.43 +/- .23, respectively (p = .024). Subjects and controls did not differ in terms of age, spirometric parameters, or duration of injury. CONCLUSIONS The results suggest that chronic therapy with baclofen diminishes cough reflex sensitivity in subjects with C-SCI. The clinical significance of this finding remains to be elucidated.
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Affiliation(s)
- P V Dicpinigaitis
- Department of Medicine, Albert Einstein College of Medicine, and the Spinal Cord Pulmonary Research Center, Veterans Affairs Medical Center, Bronx, NY, USA
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Karlsson JA, Fuller RW. Pharmacological regulation of the cough reflex--from experimental models to antitussive effects in Man. Pulm Pharmacol Ther 1999; 12:215-28. [PMID: 10500001 DOI: 10.1006/pupt.1999.0207] [Citation(s) in RCA: 75] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
- J A Karlsson
- Discovery Biology, Rhone-Poulene Rorer, Dagenham, UK
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