Over-the-counter antitussive medications for acute cough are among the most frequently used medications globally, but concerns have been raised over the safety profile of, for example, codeine-containing mixtures. Should doctors be concerned about this and, if so, which medicines are the safest?

If a cough lasts for longer than 8 weeks, it is classified as a chronic cough that is indicative of a persistent condition requiring referral and/or admission to a hospital ward.

Cough is one of the most common symptoms for which patients seek medical attention from primary care physicians and pulmonologists, probably because cough can so profoundly and adversely affect the quality of patients’ lives. Cough is both an important physiological reflex protecting the airways, and a frequent complaint associated with virtually all pulmonary and several extrapulmonary diseases. Cough is also a contributing factor in the spreading of infectious disease, such as tuberculosis.

Clinical evidence suggests that acute cough is almost always the result of a respiratory tract infection, with viruses causing approximately 90% of these. Viral respiratory tract infection is the major cause for acute cough in children and coughs associated with respiratory tract infections are usually non-productive.

Aetiology of acute cough

Although there may be a great number of causes of acute cough, the most common ones are:

  • Common cold: the most common cause of cough, it usually subsides spontaneously, in otherwise healthy persons, after 2–3 weeks.
  • Upper airways allergic disease: Hay fever, and intermittent or persistent allergic rhinitis, often in combination with sinusitis, conjunctivitis, pharyngitis and laryngitis, can also trigger acute cough. Itchy eyes and throat are usually characteristic of these diseases.
  • Intermittent asthma: Intermittent asthma, either allergic or due to infection, can cause acute cough.
  • Aspiration: Aspiration of a foreign body, most commonly in 1–3-yr-old children, as well as in elderly, fragile patients, triggers acute cough with expectoration of the foreign body, or permanent bronchial obstruction with consecutive chronic cough.
  • Acute inhalative intoxication: Workplace accidents, fires, and solvent or glue sniffing can lead to a toxic lung oedema, acute interstitial pneumonia and bronchiolitis with re-emergence of cough, often after a discomfort- and cough-free interval of 6–48 h. Immediate high-dose inhaled corticosteroid treatment should be initiated (≤100 puffs in 24 h).
  • Post-infectious cough: Post-infectious cough persists >3 weeks after an acute, often viral airway infection and resolves after <8 weeks. Epithelial damage after  pertussisor M. pneumoniae infection, or a transient increase in bronchial hyperresponsiveness (BHR), later subsiding spontaneously, are responsible for post-infectious cough.
  • Pneumonia: Pneumonia should be considered as a cause of acute cough.

Symptoms of acute cough

Most adults who present to their family practitioners with acute cough are looking for fast relief of their symptoms and, typically, these symptoms last less than three weeks. The patient might report a sudden fever or might have been in contact with an infected person. He or she will remember recent air travel or surgical procedures or being exposed to an unusual respiratory irritant (e.g., chemicals, gases, excessive tobacco smoke). The patient will usually remember wheezing. The doctor must determine whether the patient is immunosuppressed or suffers from asthma or dementia.

The patient may display signs of reduced air entry, consolidation, or restricted air entry. Acute bronchitis is usually a presumptive diagnosis, which is made based on history and examination, when the patient presents with an acute productive cough of less than 3 weeks’ duration. However, most GPs are worried that they might miss a case of acute community-acquired pneumonia (CAP), which still has relatively high mortality, especially among the elderly.

If a cough lasts for longer than 8 weeks, it is classified as a chronic cough that is indicative of a persistent condition requiring referral and/or admission to a hospital ward.

Treatment strategies

There is an array of cough preparations available for cough and cough preparations are still used extensively. Suppression of a non-productive cough such as that due to early-stage respiratory infection, may alleviate patient discomfort. Various symptomatic treatments for cough are available, including antitussives, expectorants, mucolytics, antihistamines, and bronchodilators. This article will focus on antitussive agents, which can act to reduce or interrupt the cough reflex.

Antitussives

Antitussives are remedies that allay coughing. The term ‘antitussive’ is often used specifically to refer to remedies that depress the cough reflex. Some may work by soothing irritability (respiratory demulcents); while others work by suppressing the cough centre in the medulla of the brain.

Antihistamines, demulcents and centrally-acting cough suppressants are the three main categories of antitussives. Antihistamines such as diphenhydramine and promethazine are sometimes included in cough preparations. They have a drying effect on nasal secretions and reduce the frequency of coughing. Demulcents such as simple linctus, glycerine, honey and lemon do not contain any active ingredients and have a soothing effect. Cough suppressants such as dextromethorphan, noscapine, codeine phosphate and pholcodine act directly on the coughing centre in the brain where they suppress the urge to cough.

It should be kept in mind that some cough medications contain a cough suppressant and an expectorant which have opposing effects and should not be used together.

The use of cough and cold preparations in children, particularly combination products, has come under close scrutiny owing to concerns over deaths attributed to overdose. The use of multiple combination products facilitates overdose, as parents can be easily confused by the duplication of ingredients among products.

Codeine

Codeine is the most widely used antitussive. It is a derivative of morphine which is often used in compound antitussive preparations. An association between the prenatal use of codeine and congenital malformations has not been shown although it has been demonstrated that, when codeine is used in high doses for longer periods, or near term, respiratory depression and withdrawal symptoms can occur in the neonate.

Codeine can be an effective antitussive at lower doses than required for analgesia. Therefore some of the more important side effects of codeine, such as respiratory depression, can generally be avoided at the antitussive dose. The exception appears to be young children (≤5 years of age) who may be more sensitive to the respiratory depression. Codeine is therefore not recommended for children under the age of 2 and should be used with caution in children 2 to 5 years old.

Codeine is one of the most often abused medications in South Africa, mostly due to its availability. Despite SAHPRA rescheduling codeine in 2015, it is still far easier to obtain than opiates like oxycodone and morphine. Data published in the South African Medical Journal indicates that codeine use in on the increase in South Africa. Like other opiates, codeine has significant addictive potential and its use is particularly widespread among urban youth, who refer to it as ‘lean’.

It must be noted that at least two studies show no benefit from codeine in decreasing cough symptoms and the American College of Chest Physicians does not recommend its use in the treatment of upper respiratory tract infections.

Dextromethorphan

Dextromethorphan is indicated for suppressing a non-productive cough caused by chemical or mechanical respiratory tract irritation. Examples of dosage forms for dextromethorphan include syrups, liquids, suspensions, liquid filled gel caps, granules, and lozenges. Dextromethorphan is well absorbed after oral administration, with a 15- to 30-minute onset of action and a duration of effect of 3 to 6 hours. Although uncommon, adverse effects include nausea, drowsiness, vomiting, stomach discomfort, and constipation.

According to the National Institute of Drug Abuse, dextromethorphan is one of the 2 most commonly abused cough medications, especially among adolescents. When taken in large quantities, the drug may produce euphoria and hallucinations. Abuse of dextromethorphan can impair motor function and cause numbness, nausea, vomiting, tachycardia, hypertension, an increase in body temperature, and a build-up of excess acid in the body.

Dextromethorphan has also been found to have 57 drug interactions, according to Stockey’s Drug Interactions, while other pholcodine, which has a similar mode of action, only has one 1 drug interaction listed.

Pholcodine

Pholcodine is an opiate with central antitussive action used in the treatment of cough and cold symptoms in children and adults. It is a codeine derivative with centrally acting antitussive properties, but without significant analgesic activity. Its overall benefit/risk assessment has been recently reviewed by the European Medicines Agency (EMA).

A multicentre, randomised, parallel group, controlled, double-blind study was conducted to compare efficacy and tolerability of pholcodine and dextromethorphan in the treatment of acute non-productive cough. The mean reduction in daytime cough frequency was 1.4 in the pholcodine group and 1.3 in the dextromethorphan group (per protocol population) (OR: 1.44: 95% CI: 0.73-2.82).

Both active ingredients provide day and night time reduction in cough frequency. Furthermore, the results support the use of pholcodine in the treatment of acute non-productive cough with a similar efficacy vs dextromethorphan. These results support the efficacy of pholcodine in the treatment of acute non-productive cough.

Only 17 of the 129 patients reported adverse events: 6 patients with pholcodine and 11 patients with dextromethorphan. The most frequently reported adverse reactions with both pholcodine (4.8%) and dextromethorphan (7.6%) were related to the gastrointestinal system (upper abdominal pain, diarrhoea, dyspepsia, nausea and vomiting). No serious adverse events were reported and no adverse event required additional treatment. All were resolved within 2-3 days. The authors concluded that both dextromethorphan and pholcodine were well tolerated with a slightly lower incidence of adverse events with pholcodine than dextromethorphan.

The existent safety data seems to indicate that pholcodine is at least as safe as codeine, with the advantage that it does not share the same potential for addiction.

In a comparative study of single oral doses of codeine and pholcodine, it was demonstrated that, unlike codeine, pholcodine is not metabolised to morphine. Therapeutic doses of pholcodine do not cause depression of respiration, CNS excitation or other side effects associated with narcotics. Pholcodine has a selective effect on the cough centre without affecting the respiratory centre. It is also not euphorigenic, therefore psychological dependence is unlikely to be a problem. The safety profile of pholcodine use is therefore vastly superior to that of codeine-containing medications.

The functional group is at position 3 to morpholinoethyl, as in pholcodine (3-O-morpholinoethylmorphine), resulted in a compound which was absorbed and eliminated much more slowly than codeine. The tma values for pholcodine were generally in the range of 4-8 h,while the mean elimination half-life was 37 h, or approximately 16-fold longer than that of codeine. The large difference in tA, values for codeine and pholcodine may be directly related to the marked difference in volume of distribution of these drugs rather than in clearance since AUC values of free drug were similar.

There were concerns over the association of pholcodine use in Scandinavian countries and a potential risk of IgE-sensitisation to neuromuscular blocking agents (NMBAs). From a chemical point of view, pholcodine and NMBAs are believed to share the same IgE-binding epitope, which contains the quaternary ammonium ion (QAI) or its tertiary variety.

It has been shown that pholcodine induces the production of IgE antibodies to QAI-sensitising properties, therefore being an alternative source of sensitisation to NMBAs. The mechanisms by which pholcodine activates IgE synthesis are not known, but the available data indicate that the morpholino side chain that distinguishes pholcodine from morphine might be involved.

After a lengthy review process, the EMA concluded that the evidence of a link between pholcodine and NMBA-related anaphylaxis is circumstantial and not entirely consistent. The EMA further concluded that, based on currently available information, the benefits of pholcodine in the treatment of non-productive cough outweigh the risks, and that the benefit-risk balance of pholcodine-containing products in the treatment of non-productive cough is positive under normal conditions of use.

Conclusion

Among OTC cough medications for use with acute cough, pholcodine seems to have one of the better safety profiles, due to its lack of serious adverse effects. Unlike codeine, it does not metabolise into morphine and is thus far safer for everyday use. Pholcodine has also been proven to be just as effective at treating the symptoms of acute cough as dextromethorphan. Although codeine is the most widely used antitussive, there are serious concerns about its efficacy and safety profile, which family practitioners in particular need to be aware of.