Codeine

Codeine is often considered the archetypal antitussive, yet there is little evidence that it has any intrinsic activity of its own. In man, codeine acts as a prodrug, being converted to morphine in the liver by the enzyme cytochrome P450 2D6.26 Morphine has been used for centuries in the treatment of cough and indeed has been demonstrated to have efficacy in randomised controlled trials (RCTs). Experience in chronic cough suggests that morphine is only efficacious in about a third to half of patients, others having no effective relief of the symptom. Whether this is also true in the acute bronchitis and cough in common cold is unknown.

Despite its widespread use, there is very little clinical evidence supporting significant antitussive activity for orally administered codeine. In some studies, it has been reported to have no effect on cough challenge or on the sensation of urge to cough, whereas others have reported a small but significant effect.27 In two well-designed studies investigating cough due to URTIs, codeine 30 mg, followed by 4 days of dosing four times a day, had no effect greater than placebo syrup, either on an objective initial cough recording or on a subsequent self-reported cough.28 In the second study, oral codeine (50 mg) was compared with placebo syrup in 82 participants in a parallel group design using all three measures of cough assessment; again, no effect greater than that of placebo was observed.29

The cytochrome system which converts the prodrug codeine to morphine is highly polymorphic.26 Some patients are fast metabolisers converting the majority of codeine to morphine at first pass through the liver.26 In others, the slow metabolisers, very little codeine is converted. Thus, when prescribing codeine to an individual patient who has not previously used the drug, it is impossible to predict the degree of opiate effects or indeed side effects. Both overdosing or underdosing occurs in an unpredictable fashion. The European Medicines Agency has restricted the use of codeine in children for precisely this reason while the FDA are currently reviewing the use of codeine cough-and-cold medicines in children.30 ,31 Children who are fast metabolisers were observed to have dangerous levels of sedation and suppression of respiration.26 We believe that this is not just a problem in the young and that the dangers of codeine far outweigh the limited evidence of efficacy in clinical studies.

Dextromethorphan

In the domain of cough counting, which is widely regarded as being the gold standard for assessing cough by regulatory authorities such as the FDA, only dextromethorphan has been demonstrated to significantly suppress acute cough using objective measures. In the three studies reported by Parvez et al,27 451 patients were observed using acoustic cough monitors. Compared with placebo, there was a highly significant reduction in cough counts with the dose of 30 mg dextromethorphan. To demonstrate true drug effect, dextromethorphan was administered within a capsule form, thus removing the demulcent effect of syrup. This also probably explains the relatively slow onset of action seen in this study. Subsequent studies with dextromethorphan have been performed with the syrup formulation, thus combining the rapid onset of action of demulcent activity with assessed efficacy of the drug. These positive results have been confirmed in a subsequent meta-analysis.32

In the second aspect of the assessment of efficacy of antitussive medications, dextromethorphan again passes. There have been multiple studies of the pharmacodynamics and pharmacokinetics of dextromethorphan performed under a variety of cough challenge conditions.27 Citric acid challenge is the most common modality, but recently dextromethorphan was found to be superior in the capsaicin challenge model.33 Dextromethorphan is revealed to be a drug with a relatively slow onset of action peaking in efficacy after ∼2 hours. Owing to its relatively slow penetration through the blood–brain barrier and consequent retention within the central nervous system, dextromethorphan may have a prolonged antitussive activity, being significantly better than placebo after as long as 24 hours.34 Some challenge studies also show that a higher than recommended daily dose of 30 mg may be even more efficacious against cough.

It has proven to be more difficult to obtain subjective evidence for the effect of dextromethorphan in acute cough resulting from common cold infection. As with so much of the literature assessing subjective antitussive effects with a wide range of products, many of the studies are far from rigorous in their execution, using small numbers of participants, often with diverse disease and measuring symptoms without a validated methodology. Perhaps the biggest problem in any subjective measures in cough with common cold is the rapid rate of spontaneous remission in this acute illness, the large placebo effect and the demulcent effect of the syrups. In current preparations containing dextromethorphan, all of these ancillary options are used to enhance activity. Combining the three strands of evidence, it has been estimated that there is an excess antitussive activity due to dextromethorphan at the dose of 30 mg of ∼17%.32

Pentoxyverine

Pentoxyverine citrate is in use as a non-opioid central acting antitussive with very little evidence of clinical efficacy, seen in poorly designed >50 years old clinical studies. Animal studies, however, show efficacy on evoked cough by electrical stimulation or citric acid challenge.35 ,36 In our experience, animal studies are extremely poor at predicting clinical effectiveness of antitussives.

Butamirate

Butamirate preparations are widely used in Europe as OTC antitussives. Butamirate is thought to have a central mechanism which is neither chemically nor pharmacologically related to that of the opioid alkaloids. Butamirate also possesses non-specific anticholinergic and thus bronchodilator effects. Butamirate is claimed to be effective by the manufacturer in a number of double-blind, randomised, parallel group trials with codeine and other comparators, none of which were placebo controlled.37–39 The single placebo-controlled study remains unpublished and is held on file. The effects of butamirate on cough reflex sensitivity, as demonstrated by capsaicin inhalational cough challenge in normal participants, were recently studied in a placebo-controlled six-way randomised cross-over study with dextromethorphan as the positive control. All four doses of butamirate failed to demonstrate greater cough reflex suppression than placebo, whereas dextromethorphan was significantly effective.33

Levodropropizine

Levodropropizine is suggested to be a peripherally acting antitussive which is widely used in southern Europe, particularly Italy. The clinical trials supporting its use in children and adults are summarised in a recent open access meta-analysis.40 There were four studies in children and three in adults. Only two studies were placebo comparisons. The paediatric study contained 12 children41 with asthma and the adult study (n=40) is not reported in full but is contained in another meta-analysis and appears to have been performed in hospitalised patients, the majority of whom were suffering from chronic bronchitis.42 There are thus no placebo-controlled studies demonstrating the efficacy of levodropropizine in acute cough. Of the other comparator studies, only two were in acute cough.43 ,44 By far the largest, and thus contributing most to the results of the meta-analysis, was a non-randomised open observation in children.43 All treatments were claimed to be equally effective in reducing subjective measures, but since the comparators have also not been shown to be effective against placebo, little can be made of this claim.

Ambroxol

Ambroxol is the active metabolite of bromhexine and the most popular drug on the German OTC market (in 2015, 24% of the expectorant market share with an additional 1.7% for bromhexine, source: IMS OTC Report). Most references arise from the 1970s to 1980s and are related to long-term use in obstructive lung disease to prevent exacerbations or are in chronic bronchitis45 to ease expectoration. A recent review of ambroxol clinical data46 stated that, based on acceptability of study design (ie, randomised, double-blind, controlled) for short-term use in adults, only 3 out of 24 studies were acceptable.15 ,47 ,48 Only the Matthys et al15 study investigated acute respiratory tract infection in a large, four parallel arm (some 170 patients in each arm) double-blind quadruple dummy randomised design the effect of 3×30 mg ambroxol days 1–3, 2×30 mg days 4–14, 4×300 mg myrtol (a standardised phytotherapeutic distillate containing 1,18 cineol) 1–14 days and 2×250 mg cefuroxime 1–6 days versus placebo over 2 weeks. Among secondary outcomes were diary data on nightly cough and coughing bouts during the day assessed. All three treatments were similarly effective and significantly better than placebo. The remaining two studies assessed short-term treatment of chronic conditions.47 ,48 Studies in children were conducted only without a control group or versus an active comparator in an open design.

Based on these data, symptomatic efficacy of ambroxol versus placebo on cough is proven in a single RCT.

N-acetylcysteine

NAC is the second most popular drug for acute cough in Germany with 23.5% of the OTC expectorant market share in 2015 (source: IMS OTC Report), a fact sharply contrasting with the available evidence for this indication. A Cochrane Library meta-analysis of three RCTs with cough at day 7 as the main outcome is available for acute upper and lower respiratory tract infections in a paediatric population.49 Statistically significant benefit was seen but the authors felt they were ‘of little clinical relevance’. Another Cochrane review for OTC medications for acute cough in 2014 did not find any references for NAS50 nor did a MEDLINE search by the authors of this paper (search terms of N-Acetylcystein AND Cough; N-Acetylcystein AND bronchitis; Acetylcystein AND cough; Acetylcystein AND Bronchitis).

Oxomemazine

There are no published placebo-controlled, double-blind studies supporting the use of oxomemazine in cough. In a study by Pujet et al,51 oxomemazine with guaifenesin was compared in a single-blind study with clobutinol in 130 patients with ‘infectious cough’. Cough intensity as assessed by VAS was rapidly reduced in the oxomemazine group, although there was no difference in the overall rate of resolution of cough. In an uncontrolled study in 46 infants under the age of 2,52 progress was described as ‘bonne’ in half. Chapuis et al53 report uncontrolled observations of the ‘novel antihistamine’ on cough with other allergic conditions without any patient details supplied in the manuscript.

Helicidine

Helicidine is a mucoglycoprotein extracted from the snail Helix pomatia. Helicidine has been used for >50 years in France as a cough medicine. In vivo animal studies showed antitussive efficacy in the cats; however, this study was not published.54 A placebo-controlled study in adult hospitalised patients with various diagnoses and an observational study in children were also not published.54 Studies from the 1950s claim antibacterial effects against Haemophilus (now called Bordetella) pertussis.55 A placebo syrup-controlled study54 with objective overnight cough counting in the sleep laboratory in n=30 patients with chronic obstructive pulmonary disease and objectively documented night-time cough was also performed. For the co-primary outcomes cough frequency and cough duration, an almost 50% higher reduction was demonstrated, while for secondary subjective outcomes no significant statistical difference was reported. Thus, there is no published clinical evidence to support helicidine's action in acute cough or acute bronchitis.

Menthol

Menthol is monoterpene produced by the peppermint plant Mentha arvensis from which most of the naturally occurring peppermint oil is extracted. Menthol's cooling activity is through the specific ‘cold’ receptor TRPM8, a member of the transient receptor potential family of nociceptors.56 It is primarily located on afferent sensory neurons and is anti-irritant by blockade of voltage-gated sodium channels.

Menthol has an ancient history and has become a stock ingredient of many OTC preparations. Antitussive activity was commercialised by the development of a topical rub by Lunsford Richardson in 1890,57 and recent evidence indicates that the antitussive activity of menthol may reside in the activation of nasal as opposed to lung sensory afferents.58

Clinical evidence of menthol's activity is sparse with few clinical studies performed to modern standards. Challenge studies in normal participants produce a short-lived reduction in evoked cough. In a small and poorly controlled study, menthol vapour produced a decrease in capsaicin-induced cough.59 Cough induced by inhalation of citric acid was reduced in adults by inhalation of menthol vapour compared with air and pine oil control60 and in children compared with baseline challenge, but failed to reach significance when compared with placebo.61 Surprisingly, there appears to be no published clinical studies on the effect of menthol or of the many products containing it in acute cough or bronchitis.

Diphenhydramine

Diphenhydramine is a first-generation H1 antihistamine approved in some countries as an OTC antitussive, including the USA and the UK. In Germany, diphenhydramine 50 mg is approved as a hypnotic or antiemetic only. First-generation antitussives in combination with oral decongestants are recommended by the American College of Chest Physicians Evidence Based Guidelines for the treatment of cough in common cold and in the so-called upper airway cough syndrome.62 However, despite the title of those guidelines, this recommendation is based on expert opinion.63 In cough challenge studies in healthy participants64 and patients with acute viral respiratory infection (diphenhydramine combination syrup with decongestant) in adults efficacy could have been established.65 However, no symptom or objective cough monitoring-based studies are available for acute cough. There is a clear-cut discrepancy between evidence of efficacy and broad clinical use of diphenhydramine/decongestant combinations for acute cough—despite an important sedative effect (dizziness)—especially in the USA. Table 1 evaluates how European antitussives match up to the modern metrics in cough research.

Antitussives in combination cold therapy

A popular strategy to combat the multiple symptoms in acute viral URTI has been to combine active ingredients. Such a strategy is entirely logical when symptoms require different therapeutic approaches. Thus, the addition of paracetamol to an antitussive to deal both with the cough and headache or myalgia makes therapeutic sense. Similarly, the use of a sedating antihistamine for a nocturnal preparation in combination with the antitussive may well give additional benefit and symptom relief. Some combinations on the market are, however, illogical and based on a poor understanding of the pathophysiology. It is becoming increasingly recognised that there is little evidence to support expectorant activity and, indeed, some agents classified as expectorants have been reported to have anti-inflammatory,66 antioxidant67 or antitussive activity in challenge studies.68 Similarly, expectorants, although widely prescribed in combination treatments, may actually work by decreasing the cough reflex hypersensitivity and thus relieving the sensation of mucus hypersecretion. Perhaps the most interesting studies to provide insight into the mode of action of ambroxol are recent investigations into its ability to block voltage-gated sodium channels located on sensory nerves.69 Such an activity is likely to underlie the clinically important local anaesthetic properties which support the use of ambroxol in its indication for sore throat. Sodium channel blockade may also explain some of the other activities of this class of agents through the blockade of neurogenic inflammation.

Perhaps the most important consideration when using combination products is the possibility of a drug interaction, and therefore well-conducted safety and efficacy studies are required. Only studies of adequate power should be considered. As an example, Mizoguchi et al70 studied 432 participants in a placebo-controlled study of a syrup containing 15 mg dextromethorphan hydrobromide, 7.5 mg doxylamine succinate, 600 mg paracetamol and 8 mg ephedrine sulfate. The primary end point (composite of nasal congestion/runny nose/cough/pain relief scores 3 hours postdosing) showed a highly significant beneficial effect in the group given active treatment (p=0.0002). Each individual symptom score also showed statistically significant improvement 3 hours postdosing (p≤0.017). The next morning active treatment continued to show clinically and statistically significant benefits (p≤0.003). Evidence of benefit with the test syrup was also seen in the higher score for overall night-time relief (p<0.0001) and greater satisfaction on sleep (p=0.002). Adverse events were reported at half the frequency in the active treatment group compared with the placebo and there were no reported events >1% in the population. We suggest that only by the use of large well-controlled and well-designed studies such as this can combination products be recommended with any surety.

Recommended treatment strategy

• URTIs are benign and self-limiting, and therefore patients with milder symptoms can be safely reassured.

• The demulcent effect of a simple linctus/syrup such as a home remedy of honey and lemon may bring a significant reduction in the cough, albeit of a relatively short duration. This strategy should be the first choice, particularly in children.

• In isolated dry or minimally productive cough, dextromethorphan 30–60 mg per day has the best evidence base.

• When other symptoms are also present, a combination product containing adequate amounts of dextromethorphan should be considered.

• A cough persisting longer than 2 weeks requires additional diagnostic evaluation.