Comprehensive review of antitussive drugs used in Europe. Part 2



Codeine is often considered a prototypical antitussive drug, although there is little information that it has its own intrinsic activity. In humans, codeine acts as a prodrug, turning it into morphine in the liver through the action of cytochrome P450 2D6 enzymes.

Morphine has been used for the treatment of cough for centuries and has proven to be effective in randomized controlled trials (RCTs). Experience with the use of the drug in chronic cough suggests that morphine is effective only in one-third to half of the patients, while in the rest it does not alleviate the severity of this symptom. It is not known how this data applies also to acute bronchitis and cough for colds.

Despite widespread use, there is little clinical evidence in favor of pronounced antitussive activity when administered orally with codeine. Some studies have reported no effect on a cough test or a feeling of needing to clear the throat, while in other trials a slight but noticeable effect was reported.

In two studies with a qualitative design for the study of cough on the background of SARS, codeine 30 mg for 4 days 4 times a day had an effect that did not exceed the placebo effect in the form of a syrup, both according to the objective data on the initial cough and in the subsequent assessment of cough by the patients themselves.

In the second parallel group study, codeine (50 mg) p / o was compared with placebo in the form of a syrup in 82 participants using three cough assessment methods; again, the established effect did not exceed the placebo effect.T

he cytochrome system that turns the prodrug codeine into morphine has a high polymorphism.28 Some patients are fast metabolisers, converting a large part of codeine into morphine during the first passage through the liver. In other, slow metabolisers, only a small part of codeine undergoes transformation. Thus, when prescribing codeine to patients who have not previously used the drug, it is impossible to predict the degree of opiate effects or side effects. Overdose or insufficient dosage is not predictable.

The European Medical Agency has limited the use of codeine in children for precisely this reason, and the FDA is currently assessing the use of codeine-based drugs for treating cough and cold in children. In children with fast metabolizers, dangerous levels of sedation and respiratory depression were noted. In our opinion, this is not just a problem for children, but the risk associated with the use of codeine far outweighs the limited data on its effectiveness in clinical studies.


As part of counting cough episodes, which is considered the gold standard for cough assessment by regulatory agencies, including the FDA, only dextromethorphan has proven its ability to effectively suppress cough, based on this objective method. In three studies conducted by Parves et al., 451 patients were observed using acoustic monitors to monitor coughing. Compared with placebo, there was a marked reduction in cough episodes when taking dextromethorphan 30 mg.

In order to confirm the therapeutic effect, dextromethorphan was used in the form of capsules, thereby eliminating the soothing effect of the syrup. This may explain the relatively slow onset of action observed in the study. Subsequent studies of dextromethorphan were conducted using a form of syrup, which led to the rapid development of the sedative effect and effectiveness of the drug.

Such positive results were confirmed by the following meta-analysis.In the second aspect of evaluating the effectiveness of antitussive drugs, dextromethorphan also meets the requirements. Numerous studies of the pharmacodynamics and pharmacokinetics of dextromethorphan under various cough test conditions have been conducted. The test with citric acid is the most common variant, however, it has recently been proved that for dextromethorphan the test with capsaicin is more reliable. It was found that dextromethorphan has a slow onset of action, reaching a maximum after about 2 hours.

Due to the relatively slow penetration through the blood-brain barrier and subsequent retention in the central nervous system, dextromethorphan has a longer coughing effect, significantly exceeding placebo after 24 hours. Some samples have also shown that increasing the recommended dose of 30 mg may be more effective against cough.When acute cough against the background of a cold, it is more difficult to obtain subjective data on the effect of dextromethorphan.

As in many literary sources containing a subjective assessment of the antitussive efficacy of various drugs, many studies do not meet modern criteria, including a small number of participants, often with various diseases and measuring the severity of symptoms without validated methods. Probably the biggest challenge for any subjective assessment of cough with a cold is the rapid rate of spontaneous remission in a given acute illness, the pronounced placebo effect and the calming effect of syrups. In modern preparations containing dextromethorphan, all these additional options are used to increase efficiency. Combining the three directions in the evidence base, excessive antitussive activity was observed, due to dextromethorphan at a dose of 30 mg by about 17%.


Pentoxiverin citrate is used as a non-opioid antitussive agent of central action. About its clinical effectiveness there is very little information obtained from long-held clinical studies with inappropriate design more than 50 years ago. However, animal studies demonstrate efficacy in induced cough by electrical stimulation or testing with citric acid. In our experience, studies on animals with a very low probability are able to predict the clinical efficacy of antitussive drugs.


Preparations based on butamirate are widely used in European countries as generic antitussives. It is believed that butamirate has a central mechanism of action, which has neither chemical nor pharmacological relation to the action of opioid alkaloids. Butamirate also has non-specific anticholinergic effects and, therefore, bronchodilatory properties. The butamirate, according to the manufacturer, was effective in several double-blind, randomized, parallel-group studies using codeine and other comparison agents, but in all studies there was no placebo control. The only placebo-controlled study remained unpublished and is attached to the dossier. The effect of butamirate on the sensitivity of the cough reflex, according to the results of the inhaled cough test with capsaicin in healthy participants, was recently studied in a six-period, placebo-controlled, randomized, crossover study in which dextromethorphan served as a positive control.

All four doses of butamirate did not cause a more pronounced suppression of the cough reflex compared with placebo, whereas dextromethorphan was much more effective.


It is believed that levodropropizin has a peripheral effect, and this antitussive drug is widely used in the countries of southern Europe, especially in Italy. Clinical studies in support of its use in children and adults are given in a recently conducted open access analysis. Four studies were conducted with children and three with adults. Only two studies compared with placebo.

A study on children included 12 children with asthma; the study on adults (n = 40) is not complete, but it was included in another meta-analysis and, apparently, was carried out with the participation of hospitalized patients, most of whom suffered from chronic bronchitis thus, there are no placebo-controlled studies, demonstrating the effectiveness of levodropropizin with acute coughing. Among other comparative studies, only two were conducted on patients with acute cough. 44 The most large-scale and, therefore, most of the meta-analysis results, was a non-randomized open observational trial involving children. All treatments had the same efficacy in attenuating subjective measures, however, since the comparison drugs also did not show efficacy compared with placebo, this statement is of little use.


Ambroxol is the active metabolite of bromhexine and the most commonly used generic drug in Germany (in 2015 its market share in expectorants was 24% + an additional 1.7% for bromhexine, source: Report of the Intercontinental Marketing Service on Generic Drugs).

The greatest number of references are dated 1970-80s. and are associated with long-term use of the drug in obstructive pulmonary disease to prevent exacerbations and in chronic bronchitis45 to increase expectoration. A recent review of clinical data on the use of ambroxol showed that, based on the applicability of the study design (ie, randomized, double-blind, controlled) for short-term use in adults, only 3 out of 24 studies corresponded to the task. Only a trial conducted by Mattis et al. Was directed to the study of acute respiratory viral infections in a large-scale study with 4 parallel groups (approximately 170 patients in each group) who had a double-blind, randomized design under the control of four placebo.

The effects of 3×30 mg ambroxol at 1-3 days, 2×30 mg at 4-14 days, 4×300 mg of myrtol (standardized phytotherapeutic distillate containing 1.18 cineole), 1-14 days and 2×250 mg of cefuroxime in 1-6 days were compared in comparison with placebo over 2 weeks. Among the secondary outcomes, there was data from patient diaries about night cough and cough episodes on the day of evaluation. All three treatment options had similar efficacy and were significantly superior to placebo. In the course of the other two studies, short-term treatment of chronic conditions was studied.

Studies on children were conducted only without a control group or in comparison with the active comparator with an open design.Based on the available data, the symptomatic efficacy of ambroxol versus placebo for cough was proven in a single RCT.

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