Pharmacologic treatment of cough – which product to use in children?

June 2001

Numerous products are available to patients and clinicians over-the-counter (OTC) and by prescription for the treatment of cough. Contained in these numerous products is one of several available antitussive agents. While some products contain an antitussive only, most OTC and prescription products contain other active ingredients as well, namely an antihistamine and/or decongestant.

Antitussive agents

Several different antitussive agents are contained in the numerous available products – dextromethorphan, codeine, diphenhydramine, hydrocodone, benzonatate (Tessalon Perles, Forest), carbetapentane and caramiphen. Only dextromethorphan, diphenhydramine, and in some states, codeine, are available OTC. Most OTC and prescription products contain either dextromethorphan or codeine. Nearly all of these agents function centrally by depressing the medullary cough center. Diphenhydramine (an antihistamine), carbetapentane, and caramiphen additionally possess anticholinergic activity. Benzonatate, structurally related to tetracaine (a local anesthetic), anesthetizes respiratory stretch receptors, inhibiting the cough reflex. Codeine and hydrocodone are narcotic antitussives. Dextromethorphan, a nonnarcotic, centrally acting antitussive, is the most widely available (OTC or prescription) antitussive.

Efficacy

Antitussives are probably most commonly used for coughs resulting from upper respiratory tract infections (URTI), and many clinicians recommend their use for nonproductive coughs that interfere with the patient’s sleep, school or work, nutrition intake, or for coughs that result in emesis. Clinical efficacy data of antitussives from controlled clinical trials in children are lacking, compared with adult data. A randomized, blinded trial compared placebo with appropriate doses of codeine or dextromethorphan in children ages 18 months to 12 years who were seen in private pediatric practices for a significant night cough of less than 14 days’ duration. Efficacy was determined by a symptom cough score, and it was found that neither agent was superior to placebo. Forty-nine patients were included, and with the use of multiple measures of symptoms, this study was powered sufficiently to detect a treatment-induced cough reduction as large as that from the natural resolution of cough symptoms with time.

Smith and colleagues critically reviewed the literature from 1950-1991 for controlled clinical trials of treatment of common cold symptoms with OTC products in children or adults and found few well done studies to support their use in children; no studies of antitussive agents were found that met the authors’ criteria. Advantages or increased efficacy of prescription antitussives (eg, hydrocodone, carbetapentane, etc.) compared to dextromethorphan or codeine have not been demonstrated by controlled trials. Pharmacologically, the antitussive potency of dextromethorphan is nearly identical to codeine.

In 1997, the AAP Committee on Drugs published recommendations on the appropriate use of antitussives containing codeine or dextromethorphan and concluded with several points:

• No well-controlled studies supporting the use of codeine or dextromethorphan as antitussives for children have been published, and indications for their use have not been established.
• Cough due to URTI can often be treated with non-drug measures (fluids and humidity).
• Pediatric dosages of antitussives are extrapolated from adult data and thus are imprecise for children.
• Significant adverse effects of their use have been documented.
• Clinicians should tell parents and patients about these concerns.

The implications of these recommendations are significant, and it would be prudent for all pediatric clinicians to review this document in detail (see references below).

Adverse effects

As with any drug therapy, antitussives possess potential adverse effects, and some can be significant with the use of codeine or dextromethorphan. Codeine is well known to cause gastrointestinal adverse effects (nausea, vomiting, constipation), as well as central nervous system effects such as sedation and dizziness, or respiratory depression with higher doses. Use of dextromethorphan is less likely to result in these effects, although confusion and excitation have been reported. Overdoses of dextromethorphan may also cause respiratory depression. The concern of abuse potential exists with codeine and hydrocodone. Reports of abuse of dextromethorphan-containing products have also occurred. Multi-ingredient antitussive products frequently contain sympathomimetic agents (eg, pseudoephedrine), which may also result in significant adverse effects when used. Dosing errors, among the most common errors in the use of drugs in children, can additionally be problematic, especially with the narcotic antitussives. Dosing errors with the use of liquid antitussive products (small volume doses) for young children or infants have been reported to result in significant adverse effects. Diphenhydramine is a very sedating antihistamine, and additionally possesses anticholinergic-related adverse effects. Although potentially desirable, these effects can also pose problems.

Expectorants

Expectorants are an additional ingredient commonly found in many OTC and prescription antitussive products. Guaifenesin (Robitussin, Robins) is the only expectorant approved by the FDA that is available OTC or by prescription. Expectorants are supposed to thin mucous and increase its volume to allow patients to rid themselves of it. However, clinical studies do not support this notion, and many regard guaifenesin as clinically useless. Fortunately, guaifenesin has a wide safety margin. The efficacy of iodide expectorant products (eg, potassium iodide) has also been questioned.

Products available

Numerous (more than 100) products containing antitussives alone, or with nearly every imaginable combination of decongestant, antihistamine, expectorant, or other ingredient are available OTC or by prescription to patients and clinicians. More than 30 antitussive products specific for children are also available. These products differ by active ingredients included, dosage form (eg, liquid, sustained-action liquid, capsules, lozenges, tablets, chewable tablets, etc.), cost, alcohol content, sugar content and taste, among others. One of the most important factors to consider when recommending a product is the active ingredients included. Active ingredients should be sought that target the patient’s main symptoms. Using a product with additional agents (eg, decongestants) when not necessary only increases the risk of adverse effects such as excitation and interrupted sleep. Although many liquid antitussive products are alcohol-free, some do contain alcohol (up to 10% concentration). Several pediatric antitussive-only products are available (Table). Some prescription products contain the same active ingredients as products available OTC, but in increased amounts.

Due to concerns of lack of clinical efficacy, lack of established effective doses, and potential significant adverse effects of available antitussives, non-drug therapy should be recommended for children with symptomatic cough. Cool mist humidifiers provide increased humidity, which may benefit irritated airways. Humidifiers using warm water are also available, although their use entails the risk of burns if tipped over by a child. Realistically, humidifiers may also “treat” the child’s caregivers, as they may feel relief by doing something for their child. Dr. Barton Schmitt recommends other cough treatments, as outlined in his text Instructions for Pediatric Patients. These include warm liquids (eg, warm lemonade, apple juice), corn syrup for children younger than 4 years, or cough drops for older children. Schmitt states that dextromethorphan can also be used when necessary (eg, dry coughs that interfere with sleep, school, or work).

Conclusions

The antitussive medications available OTC or by prescription can be used when a child’s cough is interrupting sleep, meals, or school, or results in emesis. Productive coughs should not be treated with antitussives. Pediatric clinicians should keep in mind the concerns the AAP has expressed about these medications – that the safest and most effective doses are still not known, that non-drug therapies should be taken advantage of, and that caregivers and parents should be taught the natural history of cough and the potential dangers of antitussive medications, especially regarding infants and young children. It is imperative that clinicians also familiarize themselves with the differing ingredients in OTC and prescription products and their intelligent use (ie, not using a multi- ingredient product to treat cough only). Combining a realistic approach of human nature (ie, caregivers desiring to do something for their sick child) with the importance of teaching caregivers about the appropriate use of antitussive medications may be the best approach.

For more information:

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy, and a clinical specialist at Blank Children's Hospital, Des Moines, Iowa.
• Committee on Drugs, American Academy of Pediatrics. Use of codeine- and dextromethorphan-containing cough remedies in children. Pediatrics. 1997;99:918-920.
• Taylor JA. Efficacy of cough suppressants in children. J Pediatr. 1993;122:799-802.
• Smith MBH. Over-the-counter cold medications, a critical review of clinical trials between 1950 and 1991. JAMA. 1993;269:2258-2263.
• Gadomski A. The need for rational therapeutics in the use of cough and cold medicine in infants. Pediatrics. 1992;89:774-776.
• Hendeles L. Efficacy and safety of antihistamines and expectorants in nonprescription cough and cold preparations. Pharmacotherapy. 1993;13(2):154-158.
• Schmitt BD. Instructions for Pediatric Patients. 2nd ed. Philadelphia: WB Saunders, 1999.