Comprehensive review of antitussive drugs used in Europe. Part 3


NAC is the second most popular drug for the treatment of acute cough in Germany, its market share in generic expectorant drugs was 23.5% in 2015 (source: Report of the Intercontinental Marketing Service on Generic Drugs). This fact contrasts sharply with the available data for this indication. A meta-analysis of the three RCTs of the Cochrane Library in patients with cough on day 7 as the main outcome was conducted for infections of the upper and lower respiratory tract in children. A statistically significant benefit was noted, but the authors considered these data to be of no particular clinical significance. Another Cochrane review of generic drugs for acute cough, conducted in 2014, did not reveal any references to NAS, nor did the search for MEDLINE by the authors of this article (search terms “N-acetylcysteine ​​And Cough; N-acetylcysteine ​​And Bronchitis; Acetylcysteine ​​I Cough; Acetylcysteine ​​& Bronchitis).


There are no published, placebo-controlled, double-blind studies using oxomemazine when coughing. In a study conducted by Puzhet et al., Oxomemazine and guayfenezin were compared in the course of a simple blind study with clobutinol in 130 patients with an “infectious cough”. Cough intensity was assessed by VAS rapidly decreased in the oxomemazine group, although there were no differences in the total frequency of cough resolution. In an uncontrolled study on 46 children under 2 years of age, progress was described as “satisfactory” in half of the participants. Shapui et al. Reported on uncontrolled observations of the effect of a “new antihistamine” on cough with other allergic reactions without providing patient data.


Helicidin – mucoglycoprotein, extracted from the snail Helix pomatia. Gelitsidin more than 50 years used in France for the treatment of cough. In vivo animal studies have shown antitussive efficacy in cats; however, this study has not been published. A placebo-controlled study in adult hospitalized patients with different diagnoses, as well as an observational study involving children, also did not appear in the press. Research 1950s. claim antibacterial effect on pertussis caused by Haemophilus (now Bordetella). A study was conducted under the control of a placebo syrup with an objective cough count in a sleep study laboratory in 30 patients with chronic obstructive pulmonary disease and objectively confirmed night cough. For primary outcomes of cough frequency and duration of cough, there was an almost 50% superiority in reducing them, while for secondary subjective outcomes there were no statistically significant differences. Thus, there is no published clinical information to support the effects of gelicidin in acute cough or acute bronchitis.


Menthol is a monoterpene, obtained from peppermint Mentha arvensis, from which natural mint oil is extracted. The cooling effect of menthol is due to the specific cold receptor TRPM8, which is part of the transient receptor nociceptor family. It is located mainly in afferent sensory neurons and has an anti-irritating effect due to the blockade of potential-dependent sodium channels.

Menthol has an ancient history and is the main ingredient of many generic drugs. The antitussive efficacy was commercialized after the development of menthol ointment by Lansford Richardson in 1890, and recently obtained data showed that the antitussive effect of menthol may consist in the activation of afferent sensory neurons of the nose, and not of the lungs.

Clinical data on menthol activity are limited to several clinical studies conducted in accordance with modern standards. Provocative trials in healthy volunteers demonstrate short-term attenuation of induced cough. In a simple and poorly controlled study, a pair of menthol caused a weakening of the cough induced by capsaicin. Cough, caused by inhalation of citric acid, was reduced in adults with inhalation of menthol vapors compared with the control in which air and pine oil were inhaled, and in children compared with the initial breakdown. However, the results did not reach significance compared with placebo. Surprisingly, there are no published clinical studies of the effects of menthol and drugs based on it for acute cough or bronchitis.


Diphenhydramine – H1 is a first-generation antihistamine approved for use in some countries as a generic antitussive, including in the United States and the United Kingdom. In Germany, diphenhydramine 50 mg has been approved as a hypnotic and antiemetic. First-generation antitussive drugs in combination with oral decongestants are recommended by the American College of Chemistry Specialists in the treatment of cough for colds and the so-called cough syndrome of the upper respiratory tract. However, despite the name of this manual, this recommendation is based on expert judgment. Provocative studies on healthy volunteers and patients with acute respiratory viral infection (a combination of diphenhydramine syrup with decongestant) in adults allowed us to establish efficacy. However, for acute cough, there are no studies of symptoms or objective control of cough. There is a clear discrepancy between the data on the effectiveness and widespread use of diphenhydramine / combinations with decongestant for acute cough – despite the pronounced sedative effect (dizziness) – especially in the United States.

Cold preparations in combination therapy for colds

The combination of active ingredients is often used to combat the many symptoms of SARS. This approach is based solely on logic when symptoms require different therapeutic measures. Thus, adding paracetamol to an antitussive to combat cough and headache or muscle pain makes sense. Similarly, adding a sedative antihistamine to an overnight medication that contains an antitussive ingredient may also have additional benefits and alleviate the symptom. However, some of the combinations on the market are unfounded and compiled with a poor understanding of pathophysiological aspects. Experts are increasingly aware that there is little information in support of expectorant activity, and some drugs, regarded as expectorant, have provoked anti-inflammatory, antioxidant and antitussive properties in provocative studies. Similarly, expectorants, despite their wide use as part of combination therapy, can have an impact by reducing the sensitivity of the cough reflex and, consequently, alleviating the feeling of mucus hypersecretion. Probably the most interesting studies that allow understanding the mechanism of action of ambroxol are recent studies of its ability to suppress voltage-gated sodium channels located on sensory nerves. Such activity probably underlies the clinically significant local anesthetic properties, which favors the use of ambroxol for the treatment of sore throat. The blockade of sodium channels can also explain some other properties of this class of drugs due to the blockade of neurogenic inflammation.

Perhaps the most important aspect in the use of combined drugs is the possibility of drug interactions, so proper safety and efficacy studies are required. Only research with sufficient power should be considered. As an example, Mizoguchi et al. Examined 432 participants in a placebo-controlled study of a syrup containing 15 mg of dextromethorphan bromide, 7.5 mg of doxylamine succinate, 600 mg of paracetamol, and 8 mg of ephedrine sulfate. The primary endpoint (a set of alleviating nasal congestion / runny nose / cough / pain 3 hours after using the drug) showed a high pronounced beneficial effect in the group receiving active treatment (p = 0.0002). The rate of each individual symptom also showed a statistically significant improvement 3 hours after taking the drug (p <0.017). In the active treatment group, the following morning, continued clinical and statistical improvement was noted (p <0.003). The data on the benefits of the studied syrup were also confirmed by an increase in the index of general relief at night (p <0.0001) and higher satisfaction from sleep (p = 0.002). Unwanted effects were noted twice as rarely in the active control group as compared with placebo, and the frequency of events in this population did not exceed 1%. In our opinion, only the use of large-scale controlled studies with a proper design like this allows us to confidently recommend combination products.

Recommended therapeutic methods

  • ARVI are benign and self-healing states, therefore, patients with mild symptoms are not in danger.
  • The soothing effects of a simple cough / syrup mixture, such as those based on honey and lemon, can greatly relieve coughing, albeit for a short time. This approach is preferred, especially in children.
  • When dry or unproductive cough, dextromethorphan is most indicated 30-60 mg / day.
  • If there are additional symptoms, consider prescribing a combination drug that contains a sufficient amount of dextromethorphan.
  • A cough that persists for more than 2 weeks requires additional diagnostic evaluation.


Acute cough is the most common symptom that occurs in humans. Although, as a rule, it is a benign and self-healing state, the frequency of the consequences of acute respiratory viral infections plays a crucial role. With scientifically based treatment, a significant improvement in patient outcome can be achieved. Although there are many gaps in knowledge regarding the treatment of acute cough, improving the understanding of the mechanism of cough hypersensitivity allows you to more efficiently select a rational treatment. A better understanding of the normalization mechanism of this abnormal reflex, which makes it possible to alleviate the condition and shorten the duration of the disease, can play a key role for society as a whole.

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