Use of cough and cold products

January 2004

There may be no other area of pediatric drug therapy where the disparity between product availability and commonality of use vs. published documented evidence of efficacy is greater than with the treatment of the common cold. One can easily find hundreds of commercial products available over-the-counter (OTC) and by prescription that target symptoms of the common cold (cough-cold medications, CCM). Many of these products are specifically marketed for children. With the season for upper respiratory infections (URIs) upon us, this month’s Pharmacology Consult column will review issues surrounding the use of these products in children and the published evidence of their efficacy. Ingredients most commonly found in CCM – antihistamines, cough suppressants, and decongestants – will primarily be discussed. (For more on cold and cough treatments, see “Modest results in treating cold symptoms, but still no cure” in this issue.)

Efficacy of CCM

Overall, published evidence from well-done, controlled trials of CCM in the pediatric population is limited. This is especially true for young children, in that few published studies have evaluated CCM. Smith reviewed clinical trials of OTC CCM published between 1950 and 1991 to determine efficacy in children, adolescents and adults. Well-defined criteria were used to assess trials for scientific validity. Only two studies of children younger than 5 years of age were found that met inclusion criteria. Neither study provided evidence of benefit. Two studies evaluated CCM in older children (5 to 11 years of age), with some evidence of benefit of nasal decongestant and antitussive ingredients.

More studies evaluated CCM in adolescents and adults. Chlorpheniramine, a first-generation antihistamine commonly found in CCM, was studied in four trials and was found to be beneficial in three, by reducing nasal mucous amount or symptom score. Decongestants were shown to be beneficial in treating nasal congestion in several studies. Only one study evaluating guaifenesin (an expectorant) met inclusion criteria, with study results demonstrating no benefit in treating cough. Studies evaluating antitussives alone did not meet inclusion criteria, as all studies evaluated animal models or humans with experimentally induced cough. Six studies evaluating combination CCM products (most commonly an antihistamine plus decongestant) in adolescents and adults met inclusion criteria and suggested evidence for reducing nasal symptoms and cough, although the role for specific ingredients in reducing cough was not clear.

In a separate trial, Clemens studied an antihistamine-decongestant combination (Dimetapp) in a randomized, double-blind, placebo-controlled manner to evaluate efficacy in children aged 6 months to 5 years who were diagnosed by a physician with an upper respiratory tract infection of less than seven days duration. Fifty-nine children were evaluated and were assessed by caregivers two hours after dosing as needed for symptom improvement (rhinorrhea, nasal congestion, cough, sleep) using a standardized questionnaire. There were no significant differences in improvement among the treatment and placebo groups, except for sleep, which was more common in children receiving Dimetapp (P<.05). These results did not differ after controlling for age, sleep, or parental desire for drug therapy.

Hutton also evaluated Dimetapp for symptomatic relief in young children (6 months to 5 years) in a controlled study, and additionally studied parental desire for medication for their children and its relationship to drug efficacy. This study was included in Smith’s evaluation. Children were randomized into three groups: drug therapy, placebo, or no treatment. Dimetapp was given as a scheduled TID dose for 48 hours. Caregivers were interviewed for symptom occurrence at enrollment and again after 48 hours. Ninety-six children were enrolled. Raw scores of improvement were additionally standardized (z scoring) to allow assessment for change in improvement, as it was anticipated at enrollment that most children would improve, regardless of therapy. Over one-half (57%) of the children randomized to no therapy improved by 48 hours, compared with 71% receiving placebo and 64% receiving Dimetapp. These differences were not statistically significant. Most caregivers (67%) believed that their child would benefit from drug therapy. Parents who believed that their child needed drug therapy reported greater symptom improvement, regardless of the therapy given. When treatment category was controlled for, parents desiring medication for their children reported greater symptom improvement as compared with parents not desiring medication (P<0.05). This implies that administration of drug therapy did not even provide a beneficial placebo effect, as children receiving drug therapy faired no better than children receiving no specific therapy did.

In 1997 the AAP published a document on the use of codeine- and dextromethorphan-containing cough products. The Committee on Drugs concluded that there are no well-controlled studies demonstrating efficacy of codeine or dextromethorphan in children; available dosage guidelines are based upon data extrapolated from adults, and have not been demonstrated as safe and effective by well-done studies; serious adverse effects (eg, central nervous system depression) have been reported. The committee recommends educating patients and caregivers about these issues.

Published review articles and texts often evaluate many CCM as of unproved value when used in children, due to lack of published controlled trials for some agents (eg, cough suppressants) or lack of benefit when studied.

In Smith’s literature analysis, trials evaluating CCM in adolescents and adults produced mixed results. A variety of antihistamines were used in the 10 studies critiqued by Smith. Chlorpheniramine, an antihistamine commonly found in OTC CCM, was evaluated in four studies. Reductions in nasal mucous amount or symptom scoring were found in three studies. The remaining studies either found no benefits to antihistamines or conflicting results. It is believed that any beneficial effects resulting from antihistamines in patients with the common cold are due to anticholinergic properties, not because of inhibitory effects against histamine, which is not a significant mediator in the common cold. Beneficial effects were found with oral and nasal decongestants to adolescents or adults in several studies, including reductions in nasal symptoms and symptom scoring. However, adverse effects also were common (increased heart rate, blood pressure [BP], palpitations, dizziness). One study of guaifenesin did not produce beneficial effects and no study of antitussives was found that met Smith’s evaluation criteria.

Adverse effects

While no medication is devoid of the potential for adverse effects, the therapeutic use of a medication includes an acceptable balance between benefit and the potential for adverse effects. With limited or no data supporting the efficacy of some ingredients in CCM, the potential for adverse effects of CCM remains important. Clinically significant adverse effects have been reported in children and adults, and young children may be at increased risk. This increased risk may result from the use of relatively small liquid volume doses, increasing the potential for error, or altered pharmacokinetics of CCM ingredients in infants or young children. When administered to infants and children, antihistamines may cause paradoxical excitement, hallucinations, respiratory depression, or dystonic reactions. First-generation antihistamines (eg, chlorpheniramine, brompheniramine) commonly cause sedation, which may be considered a beneficial effect (promoting rest) or an adverse effect (sedation at school or work, or while driving). Decongestants may cause sympathomimetic stimulation (eg, increased heart rate, BP) or seizure-like activity. Nasally applied decongestants when administered for three to five days or more have the potential to result in rhinitis medicamentosa, a rebound phenomenon, resulting in continued or increased nasal congestion. Dextromethorphan may cause confusion, excitation, nervousness or irritability, and has the potential for abuse. The volatile oils camphor and menthol, which are included in some CCM as topical antitussives, may be especially toxic to young children when ingested. The above adverse effects may also present a confusing scenario for clinicians evaluating infants and children given CCM, in that the child’s presentation may appear similar to more serious illnesses (eg, seizure disorders, bacterial meningitis). Additionally, overdoses of CCM are commonly reported and have been fatal in some cases. These adverse effects have been documented in the literature.

Hundreds of CCM products are available OTC for adults and children, and some prescription products include OTC CCM ingredients (eg, guaifenesin, pseudoephedrine) in larger dosages. Many CCM products contain two or more ingredients, which may not be necessary for a patient without the symptoms the extra ingredients target. The use of multi-ingredient products increases the risk for adverse effects. A variety of combination products are available, including antihistamine and analgesic, antihistamine and decongestant, antihistamine, decongestant and analgesic, antihistamine, decongestant and antitussive, antihistamine and expectorant, among other possible combinations. Nearly all of the ingredients are available as single-ingredient products as well. Many multi-ingredient products are specifically available for children (eg, Tylenol Cold/Childrens, Sudafed Cold and Cough/Childrens, Robitussin Flu).

CCM products intended for use in children differ from adult products by having reduced concentrations of active ingredients in liquid dosage forms (allowing more accurate volume measurement) or availability in various liquids with tastes intended to be more pleasant (eg, grape), or as chewable tablets. Many products are also available in long-acting dosage forms. If clinicians are confused over the array of OTC CCM choices, it is not hard to imagine how caregivers may feel.

Conclusions

Despite the availability of numerous CCM products, published evidence from well-done clinical trials documenting their efficacy is sparse. Published evidence for the efficacy of CCM in young children does not exist. Some evidence for CCM (decongestants, antihistamines) efficacy in adolescents and adults does exist. Topically applied nasal decongestants may be beneficial for some patients with bothersome nasal congestion. Orally administered products may also yield beneficial results, although at the expense of increased systemic adverse effects. Antihistamine administration may yield some beneficial effects of reducing rhinorrhea in older children, although this is not strongly supported by published literature. There is very little support in the literature for beneficial effects of antitussive agents.

Some CCM ingredients may have additional beneficial effects, eg, acetaminophen for analgesia, sedative effects from antihistamines. Dosages of some ingredients of CCM intended for use in children are extrapolated from adult dosages, and are not soundly based upon pharmacokinetic principles. Adverse effects from CCM ingredients can be significant, even fatal, and overdosing is not uncommon.

Alternative recommendations for treating symptoms of viral URIs in infants and young children include use of nasal saline drops, bulb syringe suctioning and room air humidification for relief of nasal obstruction. It is important to stress to caregivers that nose drops should be instilled and left in place for approximately 60 seconds, before removing nasal secretions with bulb suctioning or having children blow their nose.

Numerous products are available OTC to caregivers for treating cough-cold symptoms. Because of their widespread availability, advertising, and familiarity, many OTC CCM will be used. Caregivers should be educated on their relative efficacy and potential for adverse effects. OTC CCM use should be avoided in young infants. If CCM are used in older children, caregivers should be counseled on appropriate product selection.

For more information:

• Cherry JD. The common cold. In Feign RD, Demmter G, Cherry JD, Kaplan Sl (eds.): Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia, WB Saunders Co., 2004, 140-146.
• Committee on Drugs, American Academy of Pediatrics. Use of codeine- and dextromethorphan-containing cough remedies in children. Pediatrics. 1999;99:918-920.
• Clemens CJ. Is an antihistamine-decongestant combination effective in temporarily relieving symptoms of the common cold in preschool children? J Pediatr. 1997;130:463-466.
• Gadomski A. The need for rational therapeutics in the use of cough and cold medicine in infants. Pediatrics. 1992;89:774-776.
• Smith MBH. Over-the-counter cold medications: a critical review of clinical trials between 1950 and 1991. JAMA. 1993;269:2258-2263.
• Over-the-counter (OTC) cough remedies. The Medical Letter on Drugs and Therapeutics. 2001;43:23-25.
• Hutton N. Effectiveness of an antihistamine-decongestant combination for young children with the common cold: a randomized, controlled clinical trial. J Pediatr. 1991;118:125-130.