Cough is among the most common conditions for which patients seek the advice of community pharmacists. Most cases of acute cough are a symptom of an upper respiratory tract infection (URTI) caused by one of many specialised viral pathogens. Given the frequency of acute cough, the social and economic implications of this condition are highly significant. Common cough costs the UK economy £979m a year, comprising an estimated £875m in lost productivity and £104m in costs to the NHS, through unnecessary and potentially harmful antibiotic prescribing and purchase of over-the-counter (OTC) cough remedies.
Despite the large expenditure on OTC cough remedies, evidence for efficacy is poor by modern standards. No new drug of proven efficacy has been licensed for acute cough in over 30 years. Currently available OTC medicines are all generic formulations and clinical studies using recently developed tools for assessing antitussive effects are deemed unprofitable by manufacturers. Their use is, therefore, supported by older trials of inadequate design, using unvalidated end points and frequently using data from patients with other conditions, such as lung cancer and tuberculosis. Understandably, this has led to doubts about the efficacy of these medicines.
No new drug of proven efficacy has been licensed for acute cough in over 30 years.
Question of efficacy
A Cochrane review conducted in 2014 by Smith et al. analysed 29 trials involving 4,835 patients and compared oral OTC cough preparations with placebo in children and adults suffering from acute cough in community settings. The review concluded that there was no good evidence for or against the effectiveness of OTC cough medicines, but the media reported this neutral finding as suggesting there was proof that OTC cough medicines do not work, ignoring the authors’ carefully worded caution regarding the small number of studies in each pharmacological class and that many older studies were poorly reported. As was common in studies of this era, there was a lack of information on allocation and randomisation of treatment and control groups, as well as a lack of information on the blinding of outcome measures and a lack of validation of cough outcome measures. The authors also highlighted variations in study design, in terms of treatment types, treatment durations and outcomes measured.
Smith et al.’s ‘plain language summary’ noted that these shortcomings make “evaluation of overall effectiveness of OTC cough medicines difficult” – a lack of evidence is not the same as evidence of lack of efficacy. Indeed, there is no doubt that simple measures used in proprietary and home remedies can have significant benefit through a demulcent effect. The additional benefit from pharmacotherapy has recently been extensively reviewed according to individual agents and both positive and negative outcomes evaluated. This extensive review found that, surprisingly, codeine – the archetypal antitussive – has little or no intrinsic activity, whereas menthol had a much larger evidence base for its use in the treatment of cough.
Classifying coughs as either dry or wet is outmoded
Perhaps the most bizarre aspect of the current management of acute cough is the division of cough symptomatology into a variety of arbitrary categories, such as dry, tickly, and wet/productive, by both the NHS authorities and pharmacies. When consulting with a patient who has a cough, members of the pharmacy team, having established that the cough is of short duration (acute), will usually ask whether the cough is dry or productive. Pharmacists have been educated according to this paradigm for decades, but this approach to treating cough was intended for the management of conditions such as tuberculosis, associated with significant bronchorrhea. In modern times, this continuing paradigm has led to a range of OTC cough preparations being available from pharmacies and confusion among patients, who may not know what type of cough they have and therefore which product is most suitable for them. This has more to do with brand diversification, rather than rational antitussive pharmacology.
In the opinion of several international experts, there is little difference between a dry cough and a cough that produces minimal amounts of sputum. Almost all forms of cough, including acute cough, are now recognised to result from increased sensitivity of the afferent, sensory nerves of the tenth cranial nerve — the vagus — and has been termed ‘cough hypersensitivity syndrome’. The clinical consequence of this hypersensitive state is typified by bouts of coughing, often triggered by low threshold stimuli encountered by the patient during normal daily activities, including exposure to aerosols, perfumes and odours, and a change in air temperature. This explains why, in acute cough, we have all experienced coughing on stepping outside on a cold winter’s day.
Measurement of cough reflex sensitivity has allowed insight into the effects of viral URTI on this outcome. Laboratory studies using inhalation of the pungent extract of peppers, capsaicin, have demonstrated that cough reflex sensitivity is transiently enhanced during acute viral URTI compared with the post-recovery state.
Mechanisms proposed to explain the induction of cough and cough reflex sensitivity by viral URTI include several of infection-associated airway effects, such as enhanced release of cytokines, neurotransmitters and leukotrienes, increased neural receptor levels, reduced activity of neutral endopeptidases, transient change of afferent neural activity, mucus hypersecretion and, possibly, effects on cholinergic motor pathways.
Given the accumulating evidence presented that acute cough can be considered as a condition of cough reflex hypersensitivity, the time has come to abandon the dry/wet classification of acute cough in URTI. Acute coughs caused by a viral URTI have been shown to induce cough reflex sensitivity. Therefore the goal of therapy should be to reduce this hypersensitivity and to normalise the cough reflex, rather than differentiating between a dry cough and one producing minimal amounts of sputum. When given a cough suppressant to normalise the heightened reflex sensitivity, there is no danger of the average acute cough patient (without pre-existing lung disease) drowning in phlegm because so little is produced.
As a reflection of this paradigm shift, the expectorant guaifenesin, which reduces chest congestion, has now been shown to have significant effects on cough hypersensitivity. Likewise, the antihistamine diphenhydramine, found in several proprietary cough preparations, has also been found to inhibit cough reflex sensitivity in people with acute cough. Given the demonstrated enhancement of cough reflex sensitivity during acute viral URTI changes in cough reflex sensitivity observed during randomised controlled pharmacological interventions reflect a clinically meaningful change, rather than any spontaneous variation.
The time has come to abandon the dry/wet classification of acute cough
Unmet clinical need
There remains a significant unmet clinical need when looking at appropriate treatments for cough. Although our understanding of the cough reflex and the factors leading a cough hypersensitivity have increased, particularly over the past decade, this information has only recently been translated into the development of new cough preparations supported by well designed randomised, placebo-controlled clinical trials using validated modern methodology sufficient to gain regulatory approval.
A new cough formulation, containing diphenhydramine, ammonium chloride and levomenthol in a cocoa flavoured demulcent (Unicough), has been evaluated in the multi-centre placebo-controlled Rococo study (abstract submitted for publication). This medicine has been shown to reduce the frequency of cough and night-time cough disruption significantly. The development of such medicines that have an impact on all types of cough should change the way we think about cough and how we should respond to patients’ requests for treatment of their acute cough.
Better understanding of cough physiology should also lead to the evaluation of future medicines for this common, debilitating symptom. Such badly needed research, however, is not without its challenges. These include the need for a better understanding of the changes in airway sensory nerves and the pathways that underpin the hypertussive state. Importantly, clear guidelines need to be developed in conjunction with the regulatory authorities for the validation of any new cough treatments. Advances in clinical trials design using properly validated end points should move the therapy of cough into the modern era of evidence-based medicine.
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 Data on file 2015. Rococo study summary (available on request). The study was coordinated by Dr Birring, Respiratory Consultant at Kings College. Abstract now submitted to ERS meeting Birring et al.; A randomised controlled trial of an over the counter cough medicine CS1002 for patients with URTI associated cough.
Declarations of interest: The author has received grants and funding for research and support for conference attendance from Proctor & Gamble, Bionorica, ReckittBenkiser, GlaxoSmithKline and AstraZeneca.
By Alyn H Morice
Professor Alyn H Morice is professor of respiratory medicine, Centre for Cardiovascular and Metabolic Research, Hull York Medical School, University of Hull
Source: The Pharmaceutical Journal
04 December 2016.