Lung (2012) 190:41–44 DOI 10.1007/s00408-011-9319-y
Therapeutic Options for Acute Cough Due to Upper Respiratory Infections in Children Ian M. Paul
Received: 18 July 2011 / Accepted: 13 August 2011 / Published online: 4 September 2011 Springer Science+Business Media, LLC 2011
Abstract Cough due to upper respiratory tract infections (URIs) is one of the most frequent complaints encountered by pediatric health-care providers, and one of the most disruptive symptoms for children and families. Despite the frequency of URIs, there is limited evidence to support the few therapeutic agents currently available in the United States (US) to treat acute cough due to URI. Published, well-designed, contemporary research supporting the efficacy of narcotics (codeine, hydrocodone) and US Food and Drug Administration (FDA)-approved over-the-counter (OTC) oral antitussives and expectorants (dextromethorphan, diphenhydramine, chlophedianol, and guaifenesin) is absent for URI-associated pediatric cough. Alternatively, honey and topically applied vapor rubs may be effective antitussives.
frequency at which medications are administered, there are few evidence-based and effective therapeutic options for children. Indeed, numerous expert literature reviews have concluded that many commonly used medications are either ineffective or lack sufficient evidence to justify their use [2–7]. Alternatively, new data have emerged in the past decade that offer options for pediatric health-care providers and their patients. After giving a brief historical context to pediatric antitussives and expectorants, the new data plus other contemporary clinical trials are discussed in order to give some guidance for those treating acute cough due to URI in children.
Keywords Cough Upper respiratory tract infections Child Dextromethorphan Guaifenesin
Most OTC medications, including OTC antitussives, are relatively old, having been available to patients for decades. Dextromethorphan, for example, was discovered in the 1950s [8]. Yet, it is clear that the standards for establishing medication dose and efficacy decades ago are quite different than they are today. For dose, OTC antitussives are extrapolated from the adult dose by recommending a fraction of that dose for children in different age categories (e.g., 6–11 years old: dose; 2–5 years old: dose), a practice that does not meet today’s standards recommended by the US Food and Drug Administration (FDA) [9]. Regarding the establishment of medication efficacy, one may refer to a study claiming to demonstrate the efficacy of multi-ingredient cough and cold medications. It stated in the ‘‘Discussion’’ section of that study, ‘‘the superiority of the antitussive medications over the placebo was so obvious that no statistical analysis was required’’ [10]. Clearly, such methodology would be unacceptable today. Further, a Cochrane Collaboration review of this paper found no
Introduction Upper respiratory infections (URIs) are among the most common acute illnesses for children. With no cure for the common cold available, parents and health-care providers seek symptomatic remedies for these disruptive and frequent illnesses, and 10% of children in the United States (US) take oral over-the-counter (OTC) medications weekly [1]. Yet despite the prevalence of these illnesses and the
I. M. Paul (&) Departments of Pediatrics and Public Health Sciences, HS83, Penn State College of Medicine, P.O. Box 850, Hershey, PA 17033, USA e-mail:
[email protected]
OTC Medication History and Regulation
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statistical differences between treatment groups and the placebo [5]. OTC medications are governed under the FDA monograph process. Per the FDA website, a monograph is essentially a ‘‘recipe book’’ covering acceptable ingredients, doses, formulations, and labeling [11]. The monograph for cough, cold, allergy, bronchitis, and asthmatic (CCABA) medications was first published in 1976 [12], the antitussive final monograph was published in 1987 [13], and that for expectorants was released in 1989 [14]. Four OTC oral drugs were approved under this process, dextromethorphan, diphenhydramine, chlophedianol, and guaifenesin, as were the topical products camphor and menthol. The committee that published the 1976 version was concerned about the lack of efficacy data in children and wrote, ‘‘The panel is aware that data on the use in children of most drugs in CCABA products are negligible or nonexistent. Yet, pediatric patients comprise a substantial proportion of the population that receives these OTC products … Definitive pediatric drug dosage should be derived from data obtained in clinical trials with children using protocols similar to those used in adult patients.’’
Peer-Reviewed Clinical Trials Since 1976 Despite this recognition of limited data and a call for additional trials, since the publication of the original monograph there have been surprisingly few well-conducted studies for currently available OTC or prescription antitussives and expectorants in children (Table 1). Indeed, an English language literature search of pediatric clinical trials using the conditions of cough, URI, or upper respiratory tract infection, and the ingredient keywords (dextromethorphan, diphenhydramine, chlophedianol, guaifenesin, codeine, hydrocodone, honey, vapor rub (VR), camphor, and menthol) revealed only the seven studies listed in Table 1. The first contemporary study of OTC antitussives was conducted by Korppi et al. [15] and published in 1991. Using 75 children in a double-blind study, the investigators randomized children, aged 1–10 years, to receive dextromethorphan, dextromethorphan plus albuterol, or placebo. The 3-day study asked parents to rate cough frequency and severity during the day and the night using a 4-point Likert scale. While 56% of those parents whose children received dextromethorphan plus albuterol and 66% of those whose children received dextromethorphan alone reported some to marked relief of symptoms, 73% of those in placebo group reported a similar level of improvement, demonstrating no statistically significant differences between treatment groups. The second study by Taylor et al. [16] compared nocturnal doses of dextromethorphan plus guaifenesin with
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codeine plus guaifenesin and a cherry syrup placebo over 3 nights in children 18 months to 12 years of age. In this double-blind study, the effect of each treatment on cough frequency, sleep difficulty, and post-tussive emesis as subjectively determined by parents was determined for 49 participating children. Again, neither active preparation was superior to placebo. Over a decade later, Paul et al. [17] compared single nocturnal doses of dextromethorphan, diphenhydramine, and a simple syrup placebo in 100 children, aged 2–16 years, with cough and sleep difficulty due to URI. This double-blind study was also interested in the impact of study treatment on parental sleep. Once again, there was no difference between treatment groups as subjectively rated by parents for any study outcome: cough frequency, cough severity, bothersome nature of cough, child sleep quality, and parental sleep quality. While this again was a negative study, Paul et al. [18] published a similar study 3 years later that compared single nocturnal doses of buckwheat honey, artificial honey-flavored dextromethorphan, and no treatment in 105 children over 2 years of age using the same study design and study outcomes. Comparing the 3 study groups, those treated with buckwheat honey had significantly greater symptomatic relief than those in the other study groups for all study outcomes. A second study evaluating the antitussive efficacy of honey was published by an Iranian group [19]. In a doubleblind, randomized trial, 139 children, aged 2–5 years, with URI were randomized to receive either local honey, dextromethorphan, diphenhydramine, or supportive care consisting of saline nose drops, water vapor, cleaning a blocked nose, and acetaminophen if fever existed. Using the same nocturnal subjective outcomes as the study by Paul [18], honey again provided the greatest symptomatic relief in a comparison of the four treatment groups, with significant findings of honey’s benefit compared with other individual treatment groups remaining present in pairwise group comparisons. The final study of oral medications was conducted in Turkey and compared a combination of diphenhydramine, pseudoephedrine, and acetaminophen against an acetaminophen control group among 148 children, aged 2–12 years, with acute nasopharyngitis [20]. Children were given the drugs four times daily for up to 10 days, with evaluations at days 3, 5, and 10. Though the conclusion of the study was that there was no difference between groups for a composite score of nine symptoms as evaluated subjectively by parents, the data presented in the paper do not allow for an easy interpretation of the effect of the treatments on cough as an individual symptom. In considering the collective data for the oral medications, it is important to recognize what data are missing. Notably, there are no published well-conducted studies in
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Table 1 Pediatric antitussive and expectorant studies for cough due to URI since 1976 Drug/compound
Reference
Findings
Dextromethorphan
Korppi [15]
No difference between dextromethorphan, dextromethorphan plus albuterol, and placebo for cough frequency and severity
Taylor [16]
No difference between dextromethorphan plus guaifenesin, codeine plus guaifenesin, and placebo for cough frequency, sleep difficulty, and post-tussive emesis
Paul [17]
No difference between dextromethorphan, diphenhydramine, or placebo for nocturnal cough or sleep difficulty
Paul [18]
Comparison of buckwheat honey, artificial honey-flavored dextromethorphan, and no treatment: buckwheat honey superior for cough frequency, cough severity, child sleep quality, and parent sleep quality
Shadkam [19]
Four treatment group study: honey versus dextromethorphan versus diphenhydramine versus no treatment found that honey provided greatest symptomatic relief as measured by cough frequency, cough severity, child sleep quality, parent sleep quality
Paul [17]
See above in dextromethorphan references
Unuvar [20]
No significant difference between combination product (diphenhydramine ? pseudoephedrine ? acetaminophen) and acetaminophen alone for any URI symptoms
Shadkam [19]
See above in dextromethorphan references
Diphenhydramine
Chlophedianol Guaifenesin
None Taylor [16]
See above in dextromethorphan references
Codeine
Taylor [16]
See above in dextromethorphan references
Hydrocodone
None
Honey
Paul [18]
See above in dextromethorphan references
Shadkam [19]
See above in dextromethorphan references
Paul [21]
Study comparing a VR (camphor, menthol, and eucalyptus oils in a petrolatum base) with petrolatum and no treatment found the VR to be superior for cough frequency, cough severity, nasal congestion, child sleep quality, and parent sleep quality
Vapor rub
the past 35 years evaluating hydrocodone or chlophedianol as antitussives for pediatric URI and none studying either codeine or guaifenesin as single ingredients. In addition to studies of the oral medications, one study evaluated the effect of a topical VR containing camphor, menthol, and eucalyptus oils for URI symptoms [21]. The study aimed to determine whether a single application of the VR or petrolatum was superior to no treatment for nocturnal cough, congestion, and sleep difficulty due to URI. Surveys that included questions regarding nocturnal URI symptoms were administered to parents on two consecutive days: on the day of presentation when no medication had been given the prior evening and the next day when VR ointment, petrolatum ointment, or no treatment had been applied to their child’s chest and neck prior to bedtime according to a partially double-blinded randomization scheme. Among the 138 children between 2 and 11 years of age, significant differences in improvement were detected for outcomes related to cough, congestion, and sleep difficulty, with the VR consistently scoring the best and no treatment scoring the worst. Pairwise comparisons demonstrated the superiority of VR over no treatment for all outcomes except rhinorrhea and over petrolatum for cough severity, child and parent sleep difficulty, and combined symptom score.
Petrolatum was not significantly better than no treatment for any outcome.
Conclusions While the currently available studies do show promising data to support the use of honey and VRs for children with acute cough due to URI, the contemporary data for dextromethorphan, diphenhydramine, codeine, and guaifenesin do not support their use in children; pediatric data for chlophedianol and hydrocodone are nonexistent. The contemporary data reflect relatively few studies, all of which have subjective outcomes. Ideally, in the future validated outcome measures for both subjective and objective outcomes and end points will be developed and included in clinical trials as this has limited those trials previously conducted. It would also be an advance if dosing strategies were modernized, and perhaps novel therapies that are both safe and effective will be developed to treat the extremely common condition of cough due to URI in children. Disclosure Within the past 5 years Dr. Paul has served as a consultant for the Consumer Healthcare Products Association, Procter and Gamble Company, Novartis Consumer Health, Reckitt Benckiser
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44 Healthcare International Ltd., and McNeil Consumer Health. Dr. Paul also has received research grant funding from Procter and Gamble Company.
References 1. Vernacchio L, Kelly JP, Kaufman DW, Mitchell AA (2008) Cough and cold medication use by US children, 1999–2006: results from the slone survey. Pediatrics 122:e323–e329 2. American Academy of Pediatrics Committee on Drugs (1997) Use of codeine- and dextromethorphan-containing cough remedies in children. Pediatrics 99:918–920 3. Department of Child, Adolescent Health (2001) Cough and cold remedies for the treatment of acute respiratory infections in young children. World Health Organization, Geneva 4. Schroeder K, Fahey T (2002) Should we advise parents to administer over the counter cough medicines for acute cough? Systematic review of randomised controlled trials. Arch Dis Child 86:170–175 5. Smith SM, Schroeder K, Fahey T (2008) Over-the-counter (OTC) medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev (1):CD001831. doi: 10.1002/14651858.CD001831.pub3 6. Chang AB, Glomb WB (2006) Guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines. Chest 129:260S–283S 7. Shields MD, Bush A, Everard ML, McKenzie S, Primhak R (2008) BTS guidelines: recommendations for the assessment and management of cough in children. Thorax 63(Suppl 3):iii1–iii15 8. Cass LJ, Frederik WS (1953) Evaluation of a new antitussive agent. N Engl J Med 249:132–136 9. Rodriguez W, Selen A, Avant D et al (2008) Improving pediatric dosing through pediatric initiatives: what we have learned. Pediatrics 121:530–539 10. Reece CA, Cherry AC Jr, Reece AT, Hatcher TB, Diehl AM (1966) Tape recorder for evaluation of coughs in children. Am J Dis Child 112:124–128 11. U.S. Food and Drug Administration (2011) Over-the-counter (OTC) monograph process. http://fdadrugcompliance.com/reso urces/otc/. Accessed 28 June 2011
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Lung (2012) 190:41–44 12. Department of Health, Education, Welfare, Food, Drug Administration (1976) Over-the-counter drugs: establishment of a monograph for OTC cold, cough, allergy, bronchodilator, and antiasthmatic products. Federal Regist 41:38212–38424 13. Department of Health, Education, Welfare, Food, Drug Administration (1987) Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; final monograph for OTC antitussive drug products. Fed Regist 52: 30042–30057 14. Department of Health, Education, Welfare, Food, Drug Administration (1989) Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use; expectorant drug products for over-the-counter human use; final monograph. Fed Regist 54:8494–8509 15. Korppi M, Laurikainen K, Pietikainen M, Silvasti M (1991) Antitussives in the treatment of acute transient cough in children. Acta Paediatr Scand 80:969–971 16. Taylor JA, Novack AH, Almquist JR, Rogers JE (1993) Efficacy of cough suppressants in children. J Pediatr 122:799–802 17. Paul IM, Yoder KE, Crowell KR et al (2004) Effect of dextromethorphan, diphenhydramine, and placebo on nocturnal cough and sleep quality for coughing children and their parents. Pediatrics 114:e85–e90 18. Paul IM, Beiler J, McMonagle A, Shaffer ML, Duda L, Berlin CM Jr (2007) Effect of honey, dextromethorphan, and no treatment on nocturnal cough and sleep quality for coughing children and their parents. Arch Pediatr Adolesc Med 161:1140–1146 19. Shadkam MN, Mozaffari-Khosravi H, Mozayan MR (2010) A comparison of the effect of honey, dextromethorphan, and diphenhydramine on nightly cough and sleep quality in children and their parents. J Altern Complement Med 16:787–793 20. Unuvar E, Yildiz I, Kilic A et al (2007) Is acetaminophen as effective as an antihistamine-decongestant-acetaminophen combination in relieving symptoms of acute nasopharyngitis in children? A randomised, controlled trial. Int J Pediatr Otorhinolaryngol 71:1277–1285 21. Paul IM, Beiler JS, King TS, Clapp ER, Vallati J, Berlin CM Jr (2010) Vapor rub, petrolatum, and no treatment for children with nocturnal cough and cold symptoms. Pediatrics 126:1092–1099
