Cough and Cold Treatments for Children:

Parents of young children know thatcolds are extremely common, especiallyfrom fall until spring. Colds accountfor a large number of pediatricoffice visits and telephone calls-particularlyduring "cold season." Childrenwith rhinorrhea, cough, and fevermay feel miserable. Their parentsoften lose sleep and time from workand want to do something to helptheir children get better faster. Coughand cold preparations are often seenas a likely solution. Surveys haveshown that over 50% of preschoolerswho had cough and cold symptomsin the previous month had been treatedwith 1 or more over-the-counter(OTC) cough and cold medicines.¹

Unfortunately, there is little evidencethat these OTC preparationshave therapeutic benefit in childrenwith colds.² Because colds are self-limitedand the symptoms are largelysubjective, any treatment has the potentialfor a substantial placebo effect.Just because a child recovered froma previous cold after taking an OTCpreparation does not prove thatthe drug was helpful. Many parentsnevertheless remain convinced thatthese medications helped their child.These parents may have felt surprisedand saddened recently whenthe Consumer Healthcare ProductsAssociation-which represents theleading makers of OTC cough andcold medicines-announced a voluntarywithdrawal of such products forinfants and toddlers younger than 2years.³

This withdrawal was based onthe findings of a recent FDA reviewthat identified significant concernsabout the safety of cough/cold medicationsin young children. OTCcough/cold medications and antihistaminesare in the "top 10" for exposuresreported to US poison controlcenters in children younger than 6years. During 2004-2005, for example,an estimated 1519 children younger than 2 years were treated in USemergency departments for adverseevents, including overdoses, associatedwith these medications.⁴ Severaldeaths have been attributed to toxicityof cough and cold medications, especiallyin children under 2 years.^5,6Last fall, federal health officials recommendedthat the "consult yourphysician" advice to parents on thelabels of cold and cough medicinesintended for young children be replacedby a warning not to use themedications in children under 2years unless directed to do so by ahealth care provider. The panel furtherrecommended that these medicationsnot be used in childrenyounger than 6 years.⁷

On January 17, 2008, the FDAissued its final recommendations in apublic health advisory, noting thatbecause such medications have notbeen shown to be safe or effective,they should not be used in childrenunder 2 years of age.⁸ The FDA is continuingto review the available datafor the use of cough and cold medicationsin children aged 2 to 11 years.

The American Academy of Pediatrics(AAP) has long held that OTCcough preparations are not indicatedfor use in children and supportschanges in the FDA labeling requirementsfor children's cough and coldpreparations. Such support is basedon the fact that no discernible benefitscan be shown for children andthat misdosing of these preparationsis frequent. The potential for incorrectdosing is exacerbated by the factthat there are many multi-ingredientproducts available that may lead toconfusion and unintended dosing errorsby parents. In addition, childrenunder 2 years are apparently moresensitive to the potentially fatal effectsof some of these ingredients.

Here we summarize the evidenceabout the potential benefits (or lackthereof) and possible adverse effectsof various cough/cold preparations (including decongestants, antihistamines,antitussives, expectorants, andzinc) and ancillary therapies (eg, antipyretic/analgesics, herbal preparations,ipratropium, bulb suction, salinedrops, and antibiotics).

OTC COUGH/COLDPREPARATIONS

The discomfort produced by thesymptoms of the common cold hasled to the development of over 800OTC cough and cold medications inthe United States designed to relievea variety of symptoms-primarilynasal congestion, rhinorrhea, andcough. Antihistamines, decongestants,antitussives, expectorants, herbalremedies, and analgesics or combinationsof these products are marketedin many forms. Unfortunately,little scientific evidence supports theefficacy of these products for treatingcold symptoms in children. This maybe because there is truly no benefit,or it may be because the benefits tobe measured are largely subjectiveand cannot be accurately reported bychildren, especially those youngerthan 6 years. Viral colds are self-limitedand the symptoms are so subjectivethat there is the potential for asignificant placebo effect in treatmentstudies. Adequate blinding of patient/parent and physician is critical toeliminate the placebo effect and effectivelyevaluate cold therapies forchildren. No antiviral agents effectivein treating the common cold arepresently available.

Decongestants. Systemic sympathomimeticdecongestants, includingpseudoephedrine, phenylpropanolamine,and phenylephrine, areoften used to treat nasal congestion.These agents cause vasoconstrictionthat persists for several hours. Pseudoephedrineand phenylpropanolamineare well-absorbed from the GItract, but phenylephrine undergoesextensive biotransformation, whichcauses variable bioavailability after oral administration. Adverse effectsmay include tachycardia, irritability,sleeplessness, hypertension, headaches,nausea, vomiting, dysrhythmias,seizures, and dystonic reactions.Hypertensive crises can resultin patients who receive monoamineoxidase inhibitor therapy.

Phenylpropanolamine has beenassociated with intracranial hemorrhageand stroke, leading the FDA toissue a public health advisory removingphenylpropanolamine from OTCmedications in 2000. Because pseudoephedrinecan be used illegally inthe manufacture of methamphetamine,the availability of pseudoephedrine-containing products hasbeen severely limited by federal lawsince 2005. Pseudoephedrine may bepurchased in limited quantities frombehind the counter only on presentationof a photo identification, with alog kept of all transactions.

Both pseudoephedrine andphenylpropanolamine have beenshown to be effective in adults in reducingsymptoms of the commoncold-including nasal congestion andsneezing-although many patientsexperience side effects. No studiesdocument similar benefits in children.One study of a decongestant/antihistamine combination (phenylpropanolamine/brompheniramine) inchildren found no improvement inrhinorrhea, nasal congestion, orcough for those treated when comparedwith placebo.⁹

Topical decongestants, such asoxymetazoline, appear effective in reducingnasal congestion in adults, buttheir use is limited by the developmentof significant rebound congestionwhen the medication is discontinuedafter several days' use ("rhinitismedicamentosa"). Because infantsare preferential nose breathers, thisrebound may cause obstructive apnea.The use of topical phenylephrine duringan upper respiratory tract infection(URI) did not decrease nasal obstruction and did not alter middle earpressures significantly in a study ofchildren 6 to 18 months of age.¹⁰Other topical decongestants have notbeen studied in children.

Antihistamines. Antihistaminesare commonly used to treat symptomsof the common cold, althoughresearch has clearly shown that histaminelevels do not increase duringthe common cold and that histamineis not the chemical mediator responsiblefor cold symptoms. However,mean kinin levels do increase as coldsymptoms increase in severity andare the mediators responsible forthese symptoms.

First-generation antihistamines-including triprolidine, diphenhydramine,hydroxyzine, and chlorpheniramine-are well known to affect theCNS. Adverse effects may include sedation,paradoxical excitability, dizziness,respiratory depression, and hallucination.GI and cardiovascular sideeffects, including tachycardia, heartblock, and arrhythmias, may also occur.First-generation antihistaminesare anticholinergic and may reducesecretions and cause dry mouth,blurred vision, and urinary retention.Overdose may cause severe CNS effects,including coma, seizures, dystonia,or psychosis.

Second-generation antihistaminesinclude terfenadine, astemizole, loratadine,and cetirizine. CNS side effects,especially sedation, are less commonwith these medications than with thefirst-generation antihistamines. Anticholinergiceffects are not seen, butserious CNS or cardiovascular impairmentmay result from overdose.

Studies in adults suggest thatfirst-generation antihistamines providemodest symptomatic relief. Onestudy of chlorpheniramine in adultsshowed a 35% to 40% reduction insymptoms, with significantly lesssneezing and higher mucociliaryclearance rates, but no improvementin objective measures of nasal congestion or eustachian tube dysfunction.¹¹ Patients treated with chlorpheniraminein another study reportedsignificantly fewer objective signsof a cold and significant improvementin symptoms compared with thosetreated with placebo.¹² Similarly, amulticenter placebo-controlled trialshowed that chlorpheniramine decreasednasal discharge, sneezing,nose-blowing, and the duration ofsymptoms of the common cold inadults.¹³ It may be that the anticholinergiceffects of first-generationantihistamines resulted in decreasednasal secretions and apparent benefit.

There are few well-designedstudies of antihistamine use in children.In children, a randomized,double-blind, placebo-controlled trialof an antihistamine/decongestantcombination (brompheniramine andphenylpropanolamine) showed noimprovement in symptoms (cough,rhinorrhea, nasal congestion) in thetreated group.⁹ However, half of thetreated children were asleep 2 hoursafter treatment, and more than half ofthe children were better 2 days later-regardless of treatment group.⁹In another study, the incidence ofacute otitis media in children withURIs did not decrease with the use ofan antihistamine and decongestantcombination.¹⁴

Antitussives. Although thecough reflex is beneficial (clearingexcessive secretions and maintainingairway patency), cough is a majorconcern of parents. A significantworsening of the patient's respiratorystatus from inspissation of mucousplugs may result from cough suppressionand may be particularlyharmful in patients with asthma, pertussis,or cystic fibrosis.

Narcotic cough syrups containingcodeine or hydrocodone arethought to act centrally at the coughcenter in the brain stem. Even narcoticcough suppressants cannot completelysuppress cough in adults.Common side effects include nausea,vomiting, constipation, dizziness, andpalpitations. Respiratory depressionmay also occur and is directly relatedto the dose administered; apnea anddeath may result. Infants are particularlysensitive to these effects and maybe at greater risk for apnea. This mayresult from the fact that codeine isconjugated in the liver and these pathwaysmay not be fully developed in infants-especially in those youngerthan 6 months. Nalaxone can be usedto reverse respiratory depression.

Dextromethorphan, a narcoticanalog, has been shown to be as effectiveas codeine for cough suppressionin adults. When used in appropriatedoses, dextromethorphan hasfew CNS effects, but overdose cancause respiratory depression. Onestudy reported no difference amongplacebo, dextromethorphan, and codeinein children aged 18 months to12 years with cough; also, cough improvedafter 3 days in all childrenregardless of treatment group.¹⁵ Arecent study found that when comparedwith placebo, neither dextromethorphannor diphenhydraminehad any significant effect on coughfrequency, sleep quality, cough severity,or bothersome nature of cough inchildren with cold symptoms.¹⁶ Becausethere are no well-controlledstudies documenting the efficacy ofnarcotics or dextromethorphan totreat cough in children and becauseserious adverse effects may result,the AAP currently recommends thatpediatricians educate parents and patientsabout the lack of proven efficacyand the risk of adverse effects ofthese products.¹⁷

A recent study examined the effecton a single dose of honey givenat bedtime to children with coughand URIs.¹⁸ The effects of the honeywere compared with those of eitherhoney-flavored dextromethorphan orwith no treatment. In pairwise statisticalcomparisons, the honey was no better than the dextromethorphan,and the dextromethorphan was nobetter than no treatment, but thehoney was better than no treatmentfor reducing cough frequency and fordecreasing a combined symptomscore. The sample size was relativelysmall, however, and there are concernsabout inadequate blinding andplacebo effects

Honey may represent an alternativetreatment for cough that isgenerally safe, well tolerated, and perhapseffective, but more evidence ofefficacy will be necessary before itsuse can be recommended. Honey isnot recommended for use in childrenyounger than 12 months.

Expectorants. Agents such asguaifenesin are a common ingredientin cough/cold preparations. Guaifenesinis supposed to help thin secretions,but a controlled study showedno decrease in the volume or qualityof sputum.¹⁹ When used in youngadults with natural colds, patients didreport a subjective decrease in sputumquantity and thickness; unfortunately,however, treatment withguaifenesin did not change coughfrequency.²⁰ Many cough and coldpreparations contain both a coughsuppressant and an expectorant. Ifboth perform as advertised, the patientmay have thinned secretionsthat he or she is unable to removefrom the airway.

Zinc. In some studies withadults, treatment with zinc gluconatesignificantly decreased the durationof cold symptoms. The exact mechanismof action is unclear. In vitro, zincinhibits rhinovirus replication andmay combine with the rhinovirus tocoat proteins in such a way as to preventviral entry into the host cell.²¹Treatment seems most effective ifbegun within 24 hours of onset andrequires dosing 5 or 6 times per day.Many patients find the zinc lozengesdifficult to tolerate. A similar study inchildren 6 to 16 years old demonstrated no benefit of zinc therapy andfrequent side effects, including badtaste, nausea, irritation of the oropharynx,and diarrhea.²²

Analgesics/antipyretics. Aspirinand acetaminophen are commonlyused to treat the fever and discomfortsof the common cold. Unfortunately,studies in adults suggest thatboth aspirin and acetaminophen areassociated with increased nasalsymptoms and suppression of thehost's neutralizing antibody response.Also, treatment with aspirinhas been associated with increasedshedding of rhinovirus.^23,24

Herbal therapies. Many herbaltherapies, including echinacea, aremarketed for relief of cold symptoms.A recent meta-analysis found that echinaceatreatment decreased the likelihoodof developing a cold and also reducedthe duration of a cold.²⁵ Unfortunately,such a meta-analysis is proneto publication bias, because studiesthat found no benefit are much lesslikely to be published and included inthe meta-analysis. A recent well-controlledevaluation of echinacea in theprevention and treatment of experimentalrhinovirus infections found noclinically significant effects on the rateof infection or severity of symptoms.²⁶No known benefits of such treatmentshave been demonstrated conclusivelyin randomized controlled trials.

Herbal therapies are not approvedby the FDA and do not undergoFDA review before marketing. Inaddition, there are no official standardsof quality for purity of the preparations,labeling, toxicity information,and drug interaction information.There is only limited post-marketingsurveillance for adverse reactions.

Humidified air. Adult studiesabroad suggested that inhalation ofsteam improved nasal obstruction forup to a week following treatment andpostulated that the heated humidifiedair inhibited rhinovirus replication,leading to symptomatic improvement. Unfortunately, studies in thiscountry failed to show any benefitfrom inhaled steam; instead, the resultwas an increased duration ofsymptoms and increased nasal resistancein patients treated with steaminhalation.²⁷ Furthermore, viral sheddingof experimental rhinovirus infectionis not affected by steam inhalationtreatments.²⁸ Vapor burnsare a potential adverse effect of suchtreatment.

Menthol vapor is often added toinhalation treatments to relieve nasalcongestion. Objective evaluation ofnasal resistance using rhinometry beforeand after menthol inhalationshows no consistent effect on nasalresistance, but many patients reportsubjective improvement in nasal airflow.The use of menthol topicallymay cause chemical irritation orburns and, if ingested in excess, mentholmay cause nausea, vomiting,ataxia, and coma.

Ipratropium. This anticholinergicnasal spray effectively decreasesthe nasal discharge and sneezing ofthe common cold. It is licensed foruse in children 5 years and older, butits usefulness is limited by bothersomeside effects, including excessivedryness of the nose and throat,nosebleeds, and headache.

Bulb suction/saline drops. Bulbsuction remains a mainstay of therapyfor infants with cold symptoms. Salinenose drops used to humidify andloosen nasal mucus may improve theeffectiveness of suctioning as a kind ofreverse nose blowing. OTC salinedrops are available, but parents canmake their own supply at home lessexpensively by mixing 1/4 tsp of salt in1 cup of water.

Antibiotics. Because of the viraletiology of the common cold, antibioticshave no beneficial effect on theclinical course. Antibiotics may beuseful for the treatment of secondaryinfections, such as acute otitis mediaand sinusitis that may sometimes ac-company or follow a cold. Furthermore,antibiotics have limited effectivenessin preventing acute otitismedia among children who are otitisproneand who are treated at theonset of new cold symptoms.

Antibiotics are not effective forchildren with uncomplicated colds.Also, indiscriminate use of antibioticscan promote the development of antibiotic-resistant bacteria.

PREVENTIVE MEASURES

Because therapeutic measureshave such limited effectiveness, arethere any preventive measures thatcan be recommended?

• Breast-feeding. Breast-fed children tend to have fewer colds than children who are bottle-fed. This constitutes yet another reason to recommend breast-feeding to all mothers.

• Hand washing. Theoretically, frequent hand washing can reduce the transmission of colds. Even physicians are often poor hand washers, so the practical value of suggesting frequent hand washing for young children is extremely limited.

• Virucidal nasal tissues and hand lotions. Virucidal nasal tissues are effective in the laboratory in blocking the passage of rhinovirus from one side to the other. In controlled studies among adults with rhinovirus colds, they prevent viral hand contamination during nose-blowing and subsequent spread to others via hand contamination. Unfortunately, virucidal tissues have not been shown effective in preventing transmission of colds in the real-world family setting. The usefulness of virucidal hand lotions in preventing the hand transmission of colds remains under investigation.

• Influenza vaccinations. Immunization is moderately effective in preventing influenza, and vaccines against respiratory syncytial virus (RSV) are in development. But with more than 100 serotypes of rhinoviruses, vaccines will not soon be available to protect against this most frequent causative agent. A humanized monoclonal antibody against RSV has limited efficacy in preventing RSV infections among extremely high-risk infants (ie, extremely premature infants with bronchopulmonary dysplasia), but the high cost makes this approach totally impractical for more general use.

Recommendations

Despite the desires of patients, parents, and physicians, there iscurrently no effective pharmacological treatment of the commoncold in children. Nothing-decongestants, antihistamines, coughsuppressants, expectorants, zinc, or herbal remedies-has beenshown to have any beneficial effect in children and many maycarry a substantial risk of side effects. Even routine symptomatic therapiessuch as antipyretics and humidified air may be counterproductive.

The best medicine is education. Parents need to understand the durationand expected symptoms of the common cold, and to know what specificchanges in symptoms (eg, rapid or labored breathing) or duration(eg, a cold lasting 10 days or more without improvement) would warrant are-evaluation by their child's physician. Parents also need to be educatedabout the lack of proven efficacy and the potential side effects of availablecold remedies. Saline nose drops, adequate fluids, and use of antipyreticsfor bothersome fever may provide limited symptomatic relief-but time isstill the only known cure.

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