Introduction
Acute cough is the most common symptom for which medical advice is sought. It is responsible for over 50% of new patient attendance in primary care and is the major source of consultation in pharmacy practice. Indeed, since symptomatic therapy is the mainstay of management of this generally benign and self-limiting illness, the pharmacist is the key player in the treatment of this condition.
Unfortunately, much of the over-the-counter (OTC) therapy currently recommended throughout Europe is based on custom and practice and is not supported by clinical studies of sufficient quality to meet the standards of modern evidence-based medicine. Here we review the diagnosis and therapeutic options available for the treatment of what is perhaps the most common ailment to afflict mankind.
Acute cough in common cold and acute bronchitis
A number of overlapping terms are used throughout the world to describe the clinical syndrome of acute viral upper respiratory tract infection (URTI). We suggest that the terminology below really describes different aspects of the same common syndrome.
The common cold is defined as an acute viral URTI, with symptoms of sore throat, sneezing, chilliness, nasal discharge, nasal obstruction, cough and malaise.1
Acute cough, that is a cough arbitrarily defined as being of <2 weeks duration, is one of the most common reasons for patient visits to ambulatory care.2
Acute bronchitis is a clinical term implying a self-limited inflammation of the large airways of the lung that is characterised by cough without pneumonia, the latter being diagnosed by focal consolidation on examination or on chest X-ray.3
It is now recognised that distinguishing between acute cough due to acute bronchitis and/or common cold is not practicable.4 ,5 Only slight pathological differences, if any, exist due to the principal localisation of viruses infecting the respiratory tract. Epidemiological surveys have shown that acute cough in otherwise healthy adults is a self-limiting disease with an average duration of the main symptom, cough of 14 days.6 In children, however, acute cough can last an average of 25 days.7
Acute bronchitis is caused by viruses (∼50% rhinovirus infection) in at least 90% of cases.8 For these infections, no curative (antiviral) treatment exists and antibiotic therapy has been repeatedly shown to be ineffective in patients without pre-existing lung disease.9 Despite being a self-limiting disease, acute bronchitis poses both a high symptom burden to individuals and a high financial burden to society, mainly due to work and school absenteeism. Over 50% of new patient consultations to primary care are due to acute cough and up to 85% of cases are erroneously treated with antibiotics—with no impact on recovery.10 Apparent success is due to rapid spontaneous recovery and a huge placebo effect.11 Unnecessary and uncontrolled use of antibiotics in acute bronchitis contributes to an impending doom of antibiotic resistance.12
Acute cough due to viral respiratory tract infections
In viral respiratory tract infections, sore throat, headache, sneezing, runny nose and nasal congestion appear early in the course of the disease; cough emerges on day 2 or 3 only, but subsequently, from day 4 cough becomes the most bothersome and by far the longest lasting symptom until day 14.13–15
Viral infections of the respiratory epithelium cause early release of many inflammatory mediators disrupting the respiratory epithelium, sensitising chemosensitive cough receptors and the neuronal pathway of the cough reflex.16 ,17 Thus, hypersensitivity of the afferent sensory nerves is thought to be the major mechanism causing cough in acute bronchitis, not the production of excessive mucus. Where mild-to-moderate mucus hypersecretion occurs, it is through the superficial goblet cells and submucosal glands.18 The incidence of mucus production, if any, seems to be present in common colds in just the first 48–72 hours. An evaluation of the placebo arms (n=774) of several studies in common cold after day 1 show no increase in sputum production.19 Thus, in viral respiratory tract infections, sputum expectoration, if any, lasts for a short time and the amount of secretion is small.20 From the therapeutic aspect, the treatment of wet and dry cough remains the same and recently a call for the removal of this classification has been made.21 Therefore, antitussives with proven efficacy might be the most appropriate treatment to relieve debilitating cough, of whatever character, in acute respiratory tract infections. Worsening bronchial obstruction may only be a risk in patients with pre-existing chronic airway obstruction.21
Much of the evidence supporting drug therapy in acute cough is old and of poor quality. There is little randomised controlled trial-based evidence which is of a modern standard. There are also well-known geographical differences in prescribing. For example, in Germany, OTC secretolytics and mucolytics such as ambroxol and N-acetylcysteine (NAS) are by far the most popular treatment with a market share as high as 47.4% of the entire common cold OTC market (source: IMS OTC Report). In contrast, in North America, OTC oral decongestant/first-generation (sedating) H1 antihistamines are used most frequently. Both strategies have little supporting evidence. Degrading mucus polymers and lowering mucus viscosity by mucolytic drugs has not been proven effective in treatment of cough in acute bronchitis.22 While first-generation antihistamines such as diphenhydramine might be effective in the treatment of cough,23 the second-generation ones are not.
How can we assess the efficacy of antitussive medications?
Since acute bronchitis and acute cough are by definition self-limiting illnesses lasting a few days, it is extremely difficult to distinguish between spontaneous remissions because of the patient getting better naturally from the effect of any medicine which has been administered. Basically, three tools have been used over the years to examine the antitussive activity of the currently marketed drugs. Subjective measures such as the visual analogue scale (VAS) or simply asking the patient whether they think their cough has improved were originally the favoured efficacy measure and many long-established preparations obtained their licence on this basis. Unfortunately, many of the studies are poorly designed with an inadequate number of patients and frequently using a mixed bag of diseases such as chronic bronchitis, tuberculosis and even lung cancer! Clearly, such studies would not be permissible in the modern era. Thus, the evidence base for many traditional antitussive preparations is extremely poor and, in our opinion, would be insufficient to make any claims of antitussive activity in terms of modern ‘evidence-based medicine’.
Two objective methods of assessing cough have been developed. First, in the 1950s, cough challenge was introduced and has been perfected as a highly accurate tool for assessing the cough reflex. The participant inhales an increasing concentration of a protussive substance such as citric acid or capsaicin—the pungent extract of red peppers. The effect of drug on their cough reflex sensitivity is then compared with that of placebo. This methodology is excellent at assessing the characteristics of the study drug, such as its time course, and is frequently used in the development of novel therapies; indeed, it is recommended by the Food and Drug Administration (FDA) as part of the submission portfolio. However, it does not always correlate with subjective measures. For example, morphine has been demonstrated to have a highly effective activity in suppressing cough in some patients, but does not seem to alter cough reflex sensitivity.
The third is a recently developed modality of assessing cough using cough counting.24 It has required a number of strides in technical development, particularly in computing power, to establish a reliable methodology using cough counters. Cough counting is now recognised as the ‘gold standard’ for assessing antitussive efficacy by the FDA. Unfortunately, since it is a recently developed technique, very few of the current OTC antitussive medications have been studied using cough counting. Indeed, only a single agent, dextromethorphan, has been demonstrated to be efficacious in this arena.25
It is best to consider the various methodologies for assessing cough as the three overlapping circles of Venn diagram (figure 1). Of the three, subjective measures have proven to be the least reliable and with a few notable exceptions have not been rigorously evaluated. We consider therefore that claims made of antitussive activity solely using subjective criteria provide insufficient evidence of efficacy, a view currently supported by the FDA.
Therefore, in an attempt to promote rational prescribing, we have reviewed the evidence for frequently used treatments in acute cough, particularly from a European perspective. We examined three aspects of drug efficacy on acute cough: the effect on the cough reflex using cough challenge, and both objective (cough recording) and subjective (ie, symptom scores, specific quality of life tools) effects on clinical outcomes.