Comprehensive review of antitussive drugs used in Europe. Part 1

Acute cough caused by acute respiratory viral infections is probably the most common disease among people. The widespread use of antibiotics in such cases is ineffective, and there is no specific therapy. Home remedies and generic drugs are the main component of treating this short-term, but debilitating condition in which cough is the most unpleasant symptom. In Europe, there are various variations in the recommendations of medical personnel for the treatment of acute cough. This is confirmed by data from previous studies conducted according to standards, which today cannot be considered legalized. Acute cough is particularly difficult to study in controlled conditions due to the high frequency of spontaneous remission and the pronounced effect of placebo. This article presents a validated modern method of evaluating the effectiveness of antitussive drugs and a review of drugs used in European countries in violation of these standards.


Acute cough is the most common symptom that requires seeking medical attention. It accounts for 50% of new requests for medical care and is the main source of advice in pharmaceutical practice. Since symptomatic therapy is the main treatment for this benign, self-healing disease, pharmacists play a key role in treating this condition.

Unfortunately, many of the generic drugs currently recommended in Europe are based on practical experience and have not passed clinical studies of sufficient quality in order to meet the standards of modern science-based medicine. Here is an overview of the diagnostic and therapeutic options for the treatment of the most common ailment of mankind.

Acute cough for colds and acute bronchitis

Throughout the world, there are several similar terms describing the clinical syndrome of acute respiratory viral infection (ARVI). From our point of view, the terminology presented below fully reflects the various aspects of the same syndrome.

The common cold is ARVI, the symptoms of which include sore throat, sneezing, chills, runny nose, nasal congestion, cough and malaise.

Acute cough, that is, a cough that has a conditional duration of <2 weeks, is one of the most common reasons for the patient to see a doctor on an outpatient basis.

Acute bronchitis is a clinical term for self-limiting inflammation of the large airways of the lungs, characterized by cough without pneumonia, which is diagnosed by focal compaction during chest radiography.

Currently, there is a perception that the differentiated diagnosis of acute cough due to acute bronchitis and / or the common cold is not advisable. There are only minor pathological differences, if any, due to the main localization of the viruses affecting the airways. Epidemiological studies have shown that acute cough in generally healthy people passes on their own for an average of 14 days. However, in children acute cough can persist on average up to 25 days.

Acute bronchitis is caused by viruses (in ~ 50% of cases, rhinovirus infection) in at least 90% of cases. For these infections, there is no radical (antiviral) treatment, and antibacterial therapy has repeatedly shown its ineffectiveness in patients in the absence of a previous lung disease.

Despite the self-limiting nature of the disease, acute bronchitis is a serious problem for the patient and requires considerable financial costs from society, mainly due to the absence of patients at work and at school. Over 50% of new visits to the doctor are mainly due to acute cough and 85% of cases are mistakenly treated with antibiotics – which do not affect recovery. Apparent success is associated with a quick spontaneous recovery and a pronounced placebo effect.

Unreasonable and uncontrolled use of antibiotics for acute bronchitis leads to increasing resistance to this type of drugs.

Acute cough on the background of acute respiratory viral infections

In acute respiratory viral infections, sore throat, headache, sneezing, runny nose, and nasal congestion occur in the early stages of the disease; cough develops only for 2-4 days, but later on for 4 days it becomes the most debilitating and most prolonged symptom, which persists for 14 days.

Viral infections of the respiratory epithelium cause an early release of many inflammatory mediators, destroying the respiratory epithelium, sensitizing the chemically sensitive cough receptors and the neural pathway of the cough reflex. Thus, the hypersensitivity of the afferent nerves, and not the overproduction of mucus, is considered the main mechanism causing cough in acute bronchitis. When hypersecretion of the mucus is mild or moderate, it is caused by superficial goblet cells and submucous glands.

The development of mucus, as a rule, occurs with a cold only in the first 48-72 hours. Evaluation of placebo groups (n = 774) in several studies of patients with a cold after 1 day did not reveal an increase in sputum discharge. Consequently, in respiratory viral infections, sputum discharge persists for a short period of time, and its quantity is insignificant. From a therapeutic point of view, the treatment of wet and dry cough remains the same, and attempts have recently been made to abandon this classification. Thus, antitussive drugs with proven efficacy can serve as an appropriate treatment method to alleviate the debilitating cough of any nature in acute respiratory viral infections. The aggravation of bronchial obstruction is a risk only for patients with previous chronic airway obstruction.

Most of the information in support of drug therapy for acute coughs is outdated and of inadequate quality. Few data are available from randomized controlled trials complying with current standards. When prescribing therapy, there are also geographical differences. For example, in Germany, generic secretolytics and mucolytics, for example, Ambroxol and N-acetylcysteine ​​(NAS) are the most commonly used drugs, the percentage of sales of which is 47.4% of the total segment of generic drugs for the treatment of colds (source: Intercontinental Marketing Report drugs). In contrast, in North America, generic first-generation oral decongestants / H-1 antihistamines (sedatives) are most commonly used. Both options have little supporting data. The destruction of mucus polymers and the reduction of its viscosity with the help of mucolytics has not proven to be effective in treating acute bronchitis.22 Although first-generation antihistamines, such as diphenhydramine, may be effective in treating cough, this cannot be said about second-generation drugs.

How to evaluate the effectiveness of antitussives

Since acute bronchitis and acute cough, by definition, are self-healing diseases lasting several days, it is very difficult to distinguish spontaneous remissions due to the natural improvement of the patient’s condition while taking any medications. Over the years, three methods have been used to evaluate the antitussive activity of modern drugs. Subjective measures, such as a visual analogue scale or a simple patient survey on cough relief, were initially the preferred method of evaluating efficacy, and many long-used drugs were approved on this basis.

Unfortunately, many studies have had an unsuccessful design and an insufficient number of patients, often with a combination of diseases such as chronic bronchitis, tuberculosis and even lung cancer! Obviously, such studies would be unacceptable today. Consequently, the scientific substantiation of many traditional antitussive drugs is too weak and, in our opinion, insufficient to claim antitussive activity from the point of view of modern “evidence-based medicine”.

Two objective cough assessment methods have been developed. First, in the 1950s. a cough test was applied, which was subsequently improved to become a very accurate means of assessing the cough reflex. The participant inhales an increasing concentration of a cough-provoking substance, for example, citric acid or capsaicin – a burning red pepper extract. The effect of the drug on the sensitivity of the cough reflex was compared with that of placebo. This method is best suited for evaluating the characteristics of a test drug, for example, a time period, and is often used in the development of new drugs; it was also recommended by the Food and Drug Administration (FDA) as part of the filing of registration documents. However, the findings do not always correlate with subjective measures. For example, morphine is highly effective in suppressing cough in some patients, but it does not alter the sensitivity of the cough reflex.

The third method was developed recently and is aimed at assessing cough by counting its episodes. Its development required several technical stages, in particular computational ability, in order to form a reliable method of counting cough episodes. Coughing episodes counting is considered the “gold standard” for evaluating FDA antitussive efficacy. Unfortunately, since this method was developed only recently, only a few generic antitussive drugs have been studied with its use. In fact, only one drug, dextromethorphan, has proven effective in this area.

Of the three methods available, subjective assessment has the least reliability, and only a few notable exceptions have been evaluated. Thus, we believe that statements about antitussive activity, using exclusively subjective criteria, provide insufficient evidence of effectiveness; This view is supported by the FDA.

So, in an attempt to improve the rational prescription of therapy, we reviewed data on commonly used drugs for acute cough, especially in European countries. We evaluated three aspects of the drug’s efficacy in acute cough: effects on the cough reflex using a cough test, and objective (registration of cough) and subjective criteria (ie, symptom indicators, specific quality assessment tools) impact on the clinical outcome.

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