Comprehensive Evidence-Based Review on European Antitussives
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BMJ Open Resp Res: first published as 10.1136/bmjresp-2016-000137 on 5 August 2016. Downloaded from Cough Comprehensive evidence-based review on European antitussives Alyn Morice,1 Peter Kardos2 To cite: Morice A, Kardos P. ABSTRACT tract infection (URTI). We suggest that the Comprehensive evidence- Acute cough caused by viral respiratory tract infections terminology below really describes different based review on European is probably the most common illness to afflict BMJ Open Resp aspects of the same common syndrome. antitussives. mankind. Despite the widespread but ineffective fi Res 2016;3:e000137. The common cold is de ned as an acute viral prescribing of antibiotics, there is no specific therapy. doi:10.1136/bmjresp-2016- URTI, with symptoms of sore throat, sneez- Home remedies and over-the-counter medicines are 000137 ing, chilliness, nasal discharge, nasal obstruc- the mainstay for treatment of this short-lived but 1 debilitating condition where cough is a major tion, cough and malaise. troublesome symptom. Across Europe, there are large Acute cough, that is a cough arbitrarily Received 21 March 2016 defined as being of <2 weeks duration, is one Accepted 28 June 2016 variations in the recommendations made by healthcare professionals for the treatment of acute cough. This of the most common reasons for patient has arisen through custom and practice based on the visits to ambulatory care.2 evidence of historical studies performed to standards Acute bronchitis is a clinical term implying a well short of what would be considered legitimate self-limited inflammation of the large airways today. Acute cough is particularly difficult to study in a of the lung that is characterised by cough controlled setting because of the high rate of without pneumonia, the latter being diag- spontaneous remission and a large placebo effect. Here nosed by focal consolidation on examination we detail the validated modern methodology used to or on chest X-ray.3 assess the efficacy of antitussives and review the drugs copyright. commonly used in Europe against these standards. It is now recognised that distinguishing between acute cough due to acute bronchitis and/or common cold is not practicable.45 Only slight pathological differences, if any, exist due to the principal localisation of viruses INTRODUCTION infecting the respiratory tract. Epidemiological Acute cough is the most common symptom for surveyshaveshownthatacutecoughinother- which medical advice is sought. It is respon- wise healthy adults is a self-limiting disease with http://bmjopenrespres.bmj.com/ sible for over 50% of new patient attendance an average duration of the main symptom, in primary care and is the major source of con- cough of 14 days.6 In children, however, acute sultation in pharmacy practice. Indeed, since cough can last an average of 25 days.7 symptomatic therapy is the mainstay of man- Acute bronchitis is caused by viruses agement of this generally benign and self- (∼50% rhinovirus infection) in at least 90% limiting illness, the pharmacist is the key player of cases.8 For these infections, no curative in the treatment of this condition. (antiviral) treatment exists and antibiotic Unfortunately, much of the over-the- therapy has been repeatedly shown to be counter (OTC) therapy currently recom- ineffective in patients without pre-existing 9 mended throughout Europe is based on lung disease. Despite being a self-limiting on September 25, 2021 by guest. Protected 1 custom and practice and is not supported by disease, acute bronchitis poses both a high Head of the Centre for fi Cardiovascular and Metabolic clinical studies of suf cient quality to meet symptom burden to individuals and a high Research, Hull York Medical the standards of modern evidence-based financial burden to society, mainly due to School, University of Hull, medicine. Here we review the diagnosis and work and school absenteeism. Over 50% of Castle Hill Hospital, therapeutic options available for the treat- new patient consultations to primary care are Cottingham, UK ment of what is perhaps the most common 2Group Practice and Centre due to acute cough and up to 85% of cases fl — for Allergy, Respiratory and ailment to af ict mankind. are erroneously treated with antibiotics Sleep Medicine at Red Cross with no impact on recovery.10 Apparent Maingau Hospital, Frankfurt, Acute cough in common cold and acute success is due to rapid spontaneous recovery Germany bronchitis and a huge placebo effect.11 Unnecessary Correspondence to A number of overlapping terms are used and uncontrolled use of antibiotics in acute Dr Alyn Morice; throughout the world to describe the clinical bronchitis contributes to an impending [email protected] syndrome of acute viral upper respiratory doom of antibiotic resistance.12 Morice A, Kardos P. BMJ Open Resp Res 2016;3:e000137. doi:10.1136/bmjresp-2016-000137 1 BMJ Open Resp Res: first published as 10.1136/bmjresp-2016-000137 on 5 August 2016. Downloaded from Open Access Acute cough due to viral respiratory tract infections Basically, three tools have been used over the years to In viral respiratory tract infections, sore throat, head- examine the antitussive activity of the currently mar- ache, sneezing, runny nose and nasal congestion appear keted drugs. Subjective measures such as the visual ana- early in the course of the disease; cough emerges on day logue scale (VAS) or simply asking the patient whether 2 or 3 only, but subsequently, from day 4 cough becomes they think their cough has improved were originally the the most bothersome and by far the longest lasting favoured efficacy measure and many long-established – symptom until day 14.13 15 preparations obtained their licence on this basis. Viral infections of the respiratory epithelium cause Unfortunately, many of the studies are poorly designed early release of many inflammatory mediators disrupting with an inadequate number of patients and frequently the respiratory epithelium, sensitising chemosensitive using a mixed bag of diseases such as chronic bronchitis, cough receptors and the neuronal pathway of the cough tuberculosis and even lung cancer! Clearly, such studies reflex.16 17 Thus, hypersensitivity of the afferent sensory would not be permissible in the modern era. Thus, the nerves is thought to be the major mechanism causing evidence base for many traditional antitussive prepara- cough in acute bronchitis, not the production of exces- tions is extremely poor and, in our opinion, would be sive mucus. Where mild-to-moderate mucus hypersecre- insufficient to make any claims of antitussive activity in tion occurs, it is through the superficial goblet cells and terms of modern ‘evidence-based medicine’. submucosal glands.18 The incidence of mucus produc- Two objective methods of assessing cough have been tion, if any, seems to be present in common colds in just developed. First, in the 1950s, cough challenge was the first 48–72 hours. An evaluation of the placebo arms introduced and has been perfected as a highly accurate (n=774) of several studies in common cold after day 1 tool for assessing the cough reflex. The participant show no increase in sputum production.19 Thus, in viral inhales an increasing concentration of a protussive sub- respiratory tract infections, sputum expectoration, if any, stance such as citric acid or capsaicin—the pungent lasts for a short time and the amount of secretion is extract of red peppers. The effect of drug on their small.20 From the therapeutic aspect, the treatment of cough reflex sensitivity is then compared with that of wet and dry cough remains the same and recently a call placebo. This methodology is excellent at assessing the for the removal of this classification has been made.21 characteristics of the study drug, such as its time course, Therefore, antitussives with proven efficacy might be the and is frequently used in the development of novel ther- most appropriate treatment to relieve debilitating apies; indeed, it is recommended by the Food and Drug copyright. cough, of whatever character, in acute respiratory tract Administration (FDA) as part of the submission port- infections. Worsening bronchial obstruction may only be folio. However, it does not always correlate with subject- a risk in patients with pre-existing chronic airway ive measures. For example, morphine has been obstruction.21 demonstrated to have a highly effective activity in sup- Much of the evidence supporting drug therapy in pressing cough in some patients, but does not seem to acute cough is old and of poor quality. There is little alter cough reflex sensitivity. randomised controlled trial-based evidence which is of a The third is a recently developed modality of assessing http://bmjopenrespres.bmj.com/ modern standard. There are also well-known geograph- cough using cough counting.24 It has required a ical differences in prescribing. For example, in number of strides in technical development, particularly Germany, OTC secretolytics and mucolytics such as in computing power, to establish a reliable methodology ambroxol and N-acetylcysteine (NAS) are by far the using cough counters. Cough counting is now recog- most popular treatment with a market share as high as nised as the ‘gold standard’ for assessing antitussive effi- 47.4% of the entire common cold OTC market (source: cacy by the FDA. Unfortunately, since it is a recently IMS OTC Report). In contrast, in North America, OTC developed technique, very few of the current OTC anti- oral decongestant/first-generation (sedating) H1 antihis- tussive medications have been studied using cough tamines are used most frequently. Both strategies have counting. Indeed, only a single agent, dextromethor- little supporting evidence. Degrading mucus polymers phan, has been demonstrated to be efficacious in this on September 25, 2021 by guest. Protected and lowering mucus viscosity by mucolytic drugs has not arena.25 been proven effective in treatment of cough in acute It is best to consider the various methodologies for bronchitis.22 While first-generation antihistamines such assessing cough as the three overlapping circles of Venn as diphenhydramine might be effective in the treatment diagram (figure 1).