AMERICAN ACADEMY of PEDIATRICS Use of Codeine- And
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AMERICAN ACADEMY OF PEDIATRICS Committee on Drugs Use of Codeine- and Dextromethorphan-Containing Cough Remedies in Children ABSTRACT. Numerous prescription and nonprescrip- tions substitute diphenhydramine or eucalyptus oil tion medications are currently available for suppression in place of codeine or dextromethorphan. Prescrip- of cough, a common symptom in children. Because ad- tion medications may substitute other narcotic verse effects and overdosage associated with the admin- agents (hydrocodone or hydromorphone) for co- istration of cough and cold preparations in children have deine and may be more addictive than codeine.2,3 In been reported, education of patients and parents about addition, many of these cough products are elixirs, the lack of proven antitussive effects and the potential 3 risks of these products is needed. which may contain up to 25% alcohol by volume. The over-the-counter availability of numerous INDICATIONS AND CONTRAINDICATIONS cough and cold preparations promotes the percep- Cough is a reflex response to mechanical, chemi- tion that such medications are safe and efficacious. cal, or inflammatory irritation of the tracheobron- Although codeine and dextromethorphan are effica- 1 chial tree mediated by sensory neurons in the air- cious for cough suppression in adults, similar effi- ways reflexly through neurons in the brainstem. cacy has not been demonstrated in children. Taylor 4 Cough serves as a physiologic function to clear air- et al conducted a randomized, controlled trial of ways of obstructive or irritating material or to warn codeine, dextromethorphan, and placebo in children of noxious substances in inspired air.1 with acute nocturnal cough without evidence of In some pathologic states (eg, asthma, bronchopul- chronic underlying lung disease (asthma, cystic fi- monary dysplasia, cystic fibrosis, and a variety of brosis, or bronchopulmonary dysplasia). Neither inflammatory conditions), excessive and/or abnor- dextromethorphan nor codeine in the dosages used mal airway secretions may be produced. The cough was significantly more effective than placebo in re- reflex serves to maintain airway patency by clearing duction of acute cough. Studies using larger dosages these secretions. Clearing of pathologic tracheobron- have not been performed. Other studies focusing chial secretions is essential to patient management exclusively on children with cough have not been 5–7 and may be enhanced by chest physiotherapy. placebo-controlled trials. To our knowledge, stud- Cough suppression may adversely affect patients ies of the use of other purportedly antitussive agents with these conditions by promoting pooling of secre- in children, such as diphenhydramine, have not been tions, airway obstruction, secondary infection, and reported in the literature. hypoxemia. Demonstration of the efficacy of antitussive prepara- Many common respiratory conditions in which tions in children is lacking, and these medications may 8 cough is prominent (eg, respiratory viral infections) be potentially harmful. Decongestant (sympathomi- are self-limited (lasting a few days). Cough may be metic) components of these mixtures administered to an expression of airway reactivity or asthma. The children have been associated with irritability, restless- cough that is associated with these conditions may ness, lethargy, hallucination, hypertension, and dys- 8 be satisfactorily managed with fluids and increased tonic reactions. The clearance and metabolism of the 9 ambient humidity (especially of value with croup). components of cough mixtures may vary with age and 10,11 When cough is persistent, it is usually secondary to disease state. Great variability in the enterohepatic infection, allergy (including asthma), environmental circulation of these drugs is noted in adults, which 3 irritants (eg, cigarette smoke, dust particles) or, oc- affects drug response, especially with repeated dosing. casionally, a foreign body. Therapy should be di- The relative immaturity of hepatic enzyme systems rected at the underlying condition for lasting benefit. that metabolize drugs in young children may enhance the risk of adverse effects of such medications, espe- ANTITUSSIVE AGENTS cially in infants younger than 6 months.9 Metabolism Most cough suppressant preparations are mar- and/or toxicity also may be altered by concurrent use 12 keted as mixtures of dextromethorphan or codeine of medications such as acetaminophen. Unfortu- with antihistamines, decongestants, expectorants, nately, the dosing guidelines for these agents are based and/or antipyretics. Some nonprescription prepara- on extrapolation from adult data without consideration of their potentially unique metabolism and disposition in children. The recommendations in this statement do not indicate an exclusive course of treatment or serve as a standard of medical care. Variations, taking into Codeine account individual circumstances, may be appropriate. PEDIATRICS (ISSN 0031 4005). Copyright © 1997 by the American Acad- In adults, codeine and dextromethorphan have emy of Pediatrics. been shown to suppress both artificially induced and 918 PEDIATRICS Vol.Downloaded 99 No. 6 June from 1997www.aappublications.org/news by guest on October 3, 2021 disease-related cough, mainly through central ner- Dosages vous system mechanisms.13 A linear relationship has Pharmacokinetic studies and demonstrations of been shown to exist between a codeine dosage in the the efficacy of cough suppression in children are range of 7.5 to 60 mg/d and a decrease in the fre- lacking. Dosages of dextromethorphan of equal an- quency of chronic cough.14 Complete suppression of titussive potency to codeine produce comparable cough was not achieved in these trials, even at the levels of central nervous system depression in highest daily dose of codeine. adults.15 The recommended dosage in children is similar to that for codeine (ie, 1 mg/kg/d divided 3 Dosage into 3 to 4 doses). Pharmacokinetic studies of codeine therapy in children are lacking. The published dosage recom- Adverse Reactions and Overdosage mendation for codeine in children is 1 mg/kg/d in Acute overdosage of cough mixtures containing four divided doses, not to exceed 60 mg/d.12 To our dextromethorphan has resulted in behavioral distur- 8 knowledge, no well-controlled studies have docu- bances, including respiratory depression. mented the safety and efficacy of this dosage. CONCLUSIONS AND RECOMMENDATIONS 1. No well-controlled scientific studies were found that Adverse Reactions and Overdosage support the efficacy and safety of narcotics (including The principal clinical manifestations of codeine codeine) or dextromethorphan as antitussives in chil- toxicity are respiratory depression and obtunda- dren. Indications for their use in children have not been 14,15 tion. In children, antitussive dosages of 3 to 5 established. mg/kg/d have produced somnolence, ataxia, miosis, 2. Suppression of cough in many pulmonary airway dis- vomiting, rash, facial swelling, and pruritis. Respira- eases may be hazardous and contraindicated. Cough tory depression requiring mechanical ventilation oc- due to acute viral airway infections is short-lived and curred in 3% of children receiving dosages greater may be treated with fluids and humidity. 16 than 5 mg/kg/d; two of these patients died. Dos- 3. Dosage guidelines for cough and cold mixtures are ex- ages of codeine less than 2 mg/kg are unlikely to be trapolated from adult data and clinical experience, and associated with significant adverse reactions. Re- thus are imprecise for children. Adverse effects and ports of adverse reactions to codeine are based on overdosage associated with administration of cough single dose ingestions; the repetitive administration and cold preparations in children are reported. Further of codeine for therapeutic purposes may be associ- research on dosage, safety, and efficacy of these prepa- ated with adverse symptoms at doses lower than a rations needs to be done in children. single dose of 5 mg/kg. In adults, glucuronide con- 4. Education of patients and parents about the lack of jugation in the liver apparently inactivates codeine, proven antitussive effects and the potential risks of but 10% of an oral dose is demethylated to form these products is needed. morphine, which is believed by some to be the active form of the drug.17 The hepatic glucoronidation path- Committee on Drugs, 1996 to 1997 way is incompletely developed in infants, which Cheston M. Berlin, Jr, MD, Chairperson places them at particular risk for adverse dose-re- D. Gail McCarver-May, MD lated effects. Furthermore, alteration of hepatic en- Daniel A. Notterman, MD zyme pathways by illness or concurrent drug ther- Robert M. Ward, MD Douglas N. Weismann, MD apy (such as acetaminophen) may further alter Geraldine S. Wilson, MD metabolism of this drug and increase the risk of drug John T. Wilson, MD toxicity.10,11 Other narcotic antitussives that are available in Liaison Representatives John March, MD cough preparations, such as hydrocodone and hy- American Academy of Child & Adolescent dromorphone, have no demonstrated advantage as Psychiatry antitussive agents compared with codeine, have sim- Donald R. Bennett, MD, PhD ilar adverse effects, and have a greater risk of depen- American Medical Association/United States dency.12 Hydrocodone and hydromorphone are clas- Pharmacopeia sified as Schedule III drugs under the Controlled Joseph Mulinare, MD, MSPH Substances Act. Centers for Disease Control & Prevention Iffath