Codein versus Placebo gegen chronischen Husten bei Kindern
Abstract
Background
Cough in children is a commonly experienced symptom that is associated with increased health service utilisation and burden to parents. The presence of chronic (equal to or more than four weeks) cough in children may indicate a serious underlying condition such as inhaled foreign body or bronchiectasis. Codeine (and derivative)‐based medications are sometimes used to treat cough due to their antitussive properties. However, there are inherent risks associated with the use of these medications such as respiratory drive suppression, anaesthetic‐induced anaphylaxis, and addiction. Metabolic response and dosage variability place children at increased risk of experiencing such side effects. A systematic review evaluating the quality of the available literature would be useful to inform management practices.
Objectives
To evaluate the safety and efficacy of codeine (and derivatives) in the treatment of chronic cough in children.
Search methods
We searched the Cochrane Airways Group Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1946 to 8 June 2016), EMBASE (1974 to 8 June 2016), the online trials registries of the World Health Organization and ClinicalTrials.gov, and the bibliographic references of publications. We imposed no language restrictions.
Selection criteria
We considered studies eligible for analysis when: the participant population included children aged less than 18 years with chronic cough (duration equal to or more than four weeks at the time of intervention); and the study design evaluated codeine or codeine‐based derivatives against placebo through a randomised controlled trial.
Data collection and analysis
Two review authors independently screened the search results to determine eligibility against a standardised criteria, and we had a pre‐planned method for analysis.
Main results
We identified a total of 556 records, of which 486 records were excluded on the basis of title and abstract. We retrieved the remaining 70 references in full to determine eligibility. No studies fulfilled the inclusion criteria of this review, and thus we found no evidence to support or oppose the use of codeine or derivatives as antitussive agents for chronic cough in children.
While chronic cough is not the same as acute cough, systematic reviews on the use of codeine efficacy for acute cough in children conclude an overall lack of evidence to support or oppose the use of over‐the‐counter cough and cold medications containing codeine (or derivatives) for treatment of acute cough in children. The lack of sufficient evidence to support the use of these medications has been consistently reaffirmed by medical experts in international chronic cough guidelines and by governing medical and pharmaceutical authorities in the USA, Europe, Canada, New Zealand, and Australia. Due to the lack of sufficient evidence to support efficacy, and the known risks associated with use ‐ in particular the increased risks for children ‐ these medications are now not recommended for children less than 12 years of age and children between 12 to 18 years with respiratory conditions.
Authors' conclusions
This review has highlighted the absence of any randomised controlled trials evaluating codeine‐based medications in the treatment of childhood chronic cough. Given the potential adverse events of respiratory suppression and opioid toxicity, national therapeutic regulatory authorities recommend the contraindication of access to codeine in children less than 12 years of age. We suggest that clinical practice adhere to clinical practice guidelines and thus refrain from using codeine or its derivatives to treat cough in children. Aetiological‐based management practices continue to be advocated for children with chronic cough.
PICOs
Laienverständliche Zusammenfassung
Codein für die Behandlung von chronischem Husten bei Kindern
Fragestellung
Wir gingen der Frage nach, ob die Behandlung mit Codein (oder mit Arzneimitteln, die aus Codein hergestellt werden) bei Kindern mit chronischem Husten (vier Wochen oder länger) verträglich und wirksam ist.
Hintergrund
Husten ist eine sehr häufige Erkrankung und einer der häufigsten Gründe einen Arzt oder einen anderen Gesundheitsdienstleister aufzusuchen. Chronischer Husten (vier Wochen oder länger) bei Kindern kann ein Anzeichen für eine ernstzunehmende Grunderkrankung sein. Codein (oder Arzneimittel, die aus Codein hergestellt werden) ist in einigen freiverkäuflichen sowie auch in einigen verschreibungspflichtigen Hustensäften enthalten. Diese Arzneimittel verwendet man, um den Husten zu lindern, obwohl mit der Anwendung bekannte Risiken verbunden sind, darunter Atemschwierigkeiten, allergische Reaktionen und Sucht. Wir wollten die Sicherheit und den Nutzen dieser Arzneimittel für die Behandlung von chronischem Husten bei Kindern untersuchen.
Suchdatum
Wir suchten nach allen Studien, die bis zum 8. Juni 2016 bereits veröffentlicht waren oder kurz davor standen.
Studienmerkmale
Wir suchten nach allen randomisierten kontrollierten Studien, in denen die Behandlung von chronischem Husten (vier Wochen oder länger) bei Kindern bis 18 Jahre mit entweder Codein (oder Arzneimittel, die aus Codein hergestellt werden) oder einem Scheinmedikament (Placebo) verglichen wurde.
Hauptergebnisse
Die Suche ergab 556 Treffer. Wir überprüften und bewerteten alle nach vorher festgelegten Einschluss‐ und Ausschlusskriterien. Wir fanden keine Studien, die geeignet waren, um sie in diesen Review aufzunehmen. Jedoch fanden wir bei unserer Suche Studien in denen die Behandlung von Kindern mit akutem Husten (zwei Wochen oder weniger) mit Codein (oder Arzneimitteln, die aus Codein hergestellt werden) untersucht wurde. In einem anderen Cochrane‐Review speziell für Kinder mit akutem Husten wurden diese Studien bereits bewertet und es wurde keine Evidenz für oder gegen die Verwendung von Codein (oder Arzneimitteln, die aus Codein hergestellt werden) gefunden. Dieser Mangel an Evidenz steht im Einklang mit internationalen Leitlinien für chronischen Husten, die empfehlen die Ursache des Hustens zu behandeln. Aufgrund der bekannten Risiken, die mit der Anwendung verbunden sind, und insbesondere der erhöhten Risiken für Kinder empfehlen Dachverbände aus den USA, Europa, Kanada, Neuseeland und Australien diese Arzneimittel für Kinder unter 12 Jahren nicht und ebensowenig für Kinder mit Atemproblemen zwischen 12 und 18 Jahren. Weil befürwortende Studien fehlen, aufgrund der Ergebnisse von Studien zu akutem Husten bei Kindern und wegen der bekannten schädlichen Nebenwirkungen schließen wir, dass Codein‐basierte Arzneimittel für die Behandlung von Kindern mit chronischem Husten nicht empfohlen werden können.
Qualität der Evidenz
Wir fanden keine Studien, daher gibt es keine Bewertung der Qualität der Evidenz.
Authors' conclusions
Background
Description of the condition
Cough is a commonly experienced symptom within the community (Chang 2015), and was identified as the leading reason for acute consultations to general practitioners in Australia between 2009 and 2010 (Britt 2010). Cough in children can be broadly categorised into acute (coughing lasting less than two weeks) or chronic (coughing duration longer than four weeks) (Chang 2006a; de Jongste 2003; Gibson 2010). The latter was the subject of this review.
Unlike acute cough (which often results from a viral infection), the aetiology of chronic cough is diverse and may indicate a serious underlying disease such as an airway abnormality or bronchiectasis. Irrespective of the type of cough or its aetiology, parents and carers often seek relief for their child's cough (Vernacchio 2008). This is not surprising as the burden of cough is multidimensional and can negatively impact individuals and their families (Anderson‐James 2014; Marchant 2008).
Description of the intervention
Codeine is derived from the Papaver somniferum, or opium poppy plant, and was first extracted in 1830 by a French chemist, Pierre‐Jean Robiquet (Kane 2007). Codeine is an alkaloid opiate compound and is predominantly used as an analgesic and antitussive (cough suppressant) agent in health care. Since the discovery of codeine, numerous opiates and semi‐synthetic derivatives have been developed and utilised for many reasons, including their antitussive properties (Kane 2007). While preparations may be prescription controlled, many of these drugs are readily available and easily accessible in combination therapies with antihistamines, antipyretics, decongestants, or expectorants as over‐the‐counter, non‐prescription cough syrups or lozenges. The ease of accessibility of such treatments has likely contributed to a perception of their safety and efficacy and has contributed to widespread use within the community (Lokker 2009).
How the intervention might work
Codeine (and derivatives) have been used as an antitussive for centuries. The medication acts primarily through opioid receptors of the central nervous system, although the exact mechanisms of action are unknown (Takahama 2007). An alternative mechanism of action is through sedation (Dickinson 2014). The pharmacodynamic properties of codeine in children are poorly understood, although there are known inherent and undesirable side effects associated with this class of antitussives.
Side effects may include respiratory depression, pruritis, rash, facial swelling, vomiting, and ataxia (Fleming 2014). Codeine is metabolised by several enzymes such as CYP3A4 and CYP2D6. The latter converts codeine to morphine, the active metabolite. There are genetic variants of CYP2D6, and rapid metabolism rates increase the risk of respiratory drive suppression and adverse effects (Committee on Drugs 1997). Individual responsiveness to codeine‐based combination therapies is unpredictable, with age, genetic make‐up, ethnicity, and disease aetiology influencing the outcome (Fleming 2014; Gadomski 1992).
There is growing international concern regarding the availability and safety of codeine, with the consequences of hyper‐metabolism, drug abuse, and the risk of anaesthetic‐induced anaphylaxis at the forefront of reform agendas (European Medicines Agency 2015; Florvaag 2012; Mattoo 1997).
Why it is important to do this review
Codeine (and derivatives)‐based antitussive agents are widely used in the paediatric population, although the mechanism of action is poorly understood. The safety and efficacy of exposure is highly variable, with children at increased risk of experiencing significant adverse effects (Gadomski 1992). The burden of cough is multifaceted, resulting not only in parental stress and worry, but also on a child's ability to participate fully within society due to school and work time loss (Marchant 2008). Rigorously evaluating the efficacy of various treatment options, including codeine and its derivatives as antitussive agents, will thus assist in clinical management and allow informed burden‐reduction treatment strategies in children.
Objectives
To evaluate the safety and efficacy of codeine (and derivatives) for the treatment of chronic cough in children.
Methods
Criteria for considering studies for this review
Types of studies
We planned to include randomised controlled trials (RCTs), quasi‐RCTs, and stratified RCTs that compared codeine (or derivatives) versus placebo. We planned to include studies reported as full text, those published as abstract only, and unpublished data.
Types of participants
Due to the differing definitions and aetiology of chronic cough between children and adults, we sought to include studies of children aged 18 years or younger with a diagnosis of chronic cough (cough lasting four or more weeks). We excluded participants with acute cough.
Types of interventions
We sought to include studies comparing medications that contained codeine or codeine derivatives versus placebo.
We included the following derivative agents in the search strategy: dihydrocodeine, nalodeine, azidocodeine, acetylcodeine, dextromethorphan, nicocodine, pholcodine, alpha‐codeimethine, 6‐succinylcodeine, 6‐codeinone, 14‐hydroxycodeine, n‐methylcodinium iodine, codeine‐7,8‐oxide, codeine‐6‐glucronide, and O(6)‐codeine methyl ether.
We planned to include the following comparisons.
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Cough mixture containing codeine or codeine derivative only as the active ingredient versus placebo.
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Cough mixture containing codeine or codeine derivative plus other active ingredient/s versus cough mixture containing placebo plus the same other active ingredient/s.
Types of outcome measures
Primary outcomes
Primary outcomes were those that reflected objective measures of treatment superiority, non‐inferiority, or inferiority, and included:
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number of children not cured at follow‐up;
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number of children who experienced a reduction in cough severity (clinically defined as a greater than 70% change in severity as per previous RCTs) (Chang 1998; Marchant 2012);
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serious adverse events (a reaction to the study drug that results in hospital admission or loss of life, or both).
Secondary outcomes
The following secondary outcome measures contribute to the strength of primary outcome analysis:
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symptoms and burden of cough as reported in cough indices such as cough quality of life scores, diary card, and cough severity index scores;
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adverse events/side effects (any event that is not considered life‐threatening and does not result in a hospital admission and would otherwise not occur without exposure to the study medication).
Reporting one or more of the outcomes listed above in the trial was not an inclusion criterion for the review.
Search methods for identification of studies
Electronic searches
We searched the following databases.
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Cochrane Airways Group Register of Trials (via the Cochrane Register of Studies): all years to 8 June 2016
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Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online: all years to 8 June 2016
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MEDLINE (Ovid): 1946 to June week 1 2016
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EMBASE (Ovid): 1974 to week 23 2016
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Trials registries (ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP))
The MEDLINE strategy is listed in Appendix 1. We adapted this strategy for use in the other databases. We searched all databases from their inception to the 8 June 2016. We searched the trials registries of ClinicalTrials.gov and WHO ICTRP all years to 9 June 2016 (Appendix 2). We placed no restrictions on the language of publication.
Searching other resources
We checked the reference lists of all relevant articles for additional references.
Data collection and analysis
Selection of studies
We uploaded electronic search results to the Covidence software platform (Covidence 2015), and summarised results using the PRISMA flow diagram (Figure 1). We identified and excluded duplicates and collated multiple reports of the same study. Two review authors (SG, HP) independently screened the titles and abstracts of all studies identified for inclusion. We excluded records on the basis of the title and abstract alone when study design was clearly defined with no ambiguity. We retrieved the full‐text publications of records that required further clarification, including those published in a language other than English. We sought translation for non‐English publications using a standardised inclusion/exclusion criteria sheet. Review authors independently recorded the reason for exclusion. Where there were discrepancies, a third person (AC) adjudicated.
PRISMA study flow diagram.
Data extraction and management
It was planned that two review authors (SG, HP) were to extract the following study characteristics from included studies.
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Methods: study design, total duration of study, details of any 'run in' period, number of study centres and location, study setting, withdrawals, and date of study.
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Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria, and exclusion criteria.
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Interventions: intervention, comparison, concomitant medications, and excluded medications.
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Outcomes: primary and secondary outcomes specified and collected, and time points reported.
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Notes: funding for trial, and notable conflicts of interest of trial authors.
However, as no studies fulfilled the inclusion criteria, data extraction was not possible.
Assessment of risk of bias in included studies
It was planned that two review authors (SG, HP) would independently assess risk of bias for each included study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We would have resolve any disagreements by discussion or by involving another review author (AC). We planned to assess the risk of bias according to the following domains.
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Random sequence generation.
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Allocation concealment.
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Blinding of participants and personnel.
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Blinding of outcome assessment.
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Incomplete outcome data.
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Selective outcome reporting.
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Other bias.
We planned to grade each potential source of bias as high, low, or unclear and provide a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We planned to summarise the 'Risk of bias' judgements across different studies for each of the domains listed. Had we identified sufficient studies, we would have considered blinding separately for different key outcomes where necessary (for example for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient‐reported pain scale). Where information on risk of bias related to unpublished data or correspondence with a trialist, we would have noted this in the 'Risk of bias' table.
When considering treatment effects, we planned to take into account the risk of bias for the studies that contributed to that outcome.
Assessment of bias in conducting the systematic review
We conducted the review according to the published protocol and reported any deviations from it in the Differences between protocol and review section of this systematic review.
Measures of treatment effect
We planned to analyse dichotomous data as odds ratios and continuous data as mean difference or standardised mean difference. We planned to enter data presented as a scale with a consistent direction of effect.
We planned to undertake meta‐analyses only where this was meaningful, that is if the treatments, participants, and underlying clinical questions were similar enough for pooling to make sense.
We would have narratively described skewed data reported as medians and interquartile ranges.
If multiple trial arms had been reported in a single trial, we would have included only the relevant arms. Where two comparisons (for example drug A versus placebo and drug B versus placebo) were combined in the same meta‐analysis, we would have halved the control group to avoid double‐counting.
Unit of analysis issues
For dichotomous data, we planned to report the proportion of participants contributing to each outcome in comparison with the total number randomised. For rate ratios of common events whereby one participant may have more than one event, we would have used generic inverse variance. We would have taken the rate ratios from the published papers and calculated the standard errors from confidence intervals (CI) or P values published in the papers. For cross‐over studies, mean treatment differences would have been calculated from raw data, extracted or imputed and entered as fixed‐effect generic inverse variance outcome, to provide summary weighted differences and 95% CIs.
Dealing with missing data
We planned to contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (for example when a study was identified as abstract only). Where this was not possible, and the missing data were thought to introduce serious bias, we would have explored the impact of including such studies in the overall assessment of results by a sensitivity analysis.
Assessment of heterogeneity
We planned to describe and test any heterogeneity between the study results to see if it reached statistical significance using a Chi2 test. We would have included the 95% CI estimated using a random‐effects model whenever there were concerns about statistical heterogeneity. We would have considered heterogeneity significant when the P value was less than 0.10 (Higgins 2011). We would have used the I2 statistic to measure heterogeneity among the trials in each analysis. Had we identified substantial heterogeneity, we would have reported this and explored possible causes by prespecified subgroup analysis.
Assessment of reporting biases
Had we been able to pool more than 10 trials, we would have created and examined a funnel plot to explore possible small‐study and publication biases and would have consulted a statistician to ensure appropriate analysis was conducted.
Data synthesis
We planned to use a random‐effects model and perform a sensitivity analysis with a fixed‐effect model.
'Summary of findings' table
We planned to create a 'Summary of findings' table reporting the following outcomes: number of children not cured at follow‐up; number of children who experienced a reduction in cough severity; serious adverse events; and symptoms and burden of cough as reported in cough indices tools. We planned to use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies that contribute data to the meta‐analyses for the prespecified outcomes. We planned to use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), using GRADEpro software (GRADEpro GDT). We planned to justify all decisions to down‐ or up‐grade the quality of studies using footnotes and make comments to aid the reader's understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
We planned to carry out the following subgroup analyses.
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Children aged less than seven years and seven years or older.
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Children with diagnosed respiratory conditions (e.g. cystic fibrosis (CF), non‐CF bronchiectasis) versus children with no diagnosed respiratory condition.
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Active ingredient other than codeine (e.g. expectorants, antihistamines, decongestants, antipyretics, substances that may soften coughing such as honey or syrup).
We planned to use the following outcomes in subgroup analyses.
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Number of children not cured at follow‐up.
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Number of children who experienced a reduction in cough severity based on objective symptom measures of sputum production, runny nose, fevers, and air entry; as well as subjective measures of cough burden.
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Serious adverse events.
We planned to use the formal test for subgroup interactions in Review Manager 5 (RevMan 2014).
Sensitivity analysis
We planned to carry out the following sensitivity analyses.
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A comparison based on 'Risk of bias' assessments.
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A comparison of available‐case analyses versus true intention‐to‐treat (ITT) analyses, when the ITT analyses were imputed with best‐case and worse‐case outcome data.
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A comparison of results from fixed‐effect models versus results from random‐effects models.
Results
Description of studies
We identified 903 records through database searching and an additional 25 records through other sources. After removing duplicates, we screened 556 records and excluded 486 records. We retrieved full‐text articles for the remaining 70 records, of which 23 were excluded due to irrelevance and 47 were excluded with reasons. We found no studies that were eligible for inclusion in this review. See Figure 1 for PRISMA diagram and the Characteristics of excluded studies table for specific details on excluded records.
Results of the search
We initially performed the Cochrane Airways Group Register of Trials literature search on 27 March 2015, and subsequently re‐ran the search on the 11 September 2015 and then again on the 8 June 2016, which yielded a total of 903 references (Figure 1). A search of ClinicalTrials.gov and the WHO ICTRP yielded an additional 25 results. After de‐duplication, we considered 556 abstracts for inclusion against the predetermined criteria.
We excluded a total of 486 studies on the basis of the abstract alone. We retrieved full‐text publications for the remaining 70 references in order to further determine inclusion eligibility. Of these, 16 articles were published in a language other than English (German, Italian, Czech, Spanish, and French). Translation was provided against a standardised inclusion/exclusion template. We deemed a total of 23 records irrelevant. The remaining 47 publications did not fulfil the inclusion criteria; reasons for exclusion are provided in the Characteristics of excluded studies table.
Included studies
There were no included studies.
Excluded studies
Reasons for exclusion of the aforementioned full‐text articles were either solely, or a combination of, the following: non‐RCT publication (n = 15); non‐placebo‐controlled study design (n = 6); studies evaluating acute cough (n = 6); and studies with an adult‐only participant population (n = 20). We excluded NCT02651116 because it did not fit our inclusion criteria (acute cough), however this study is ongoing. We have provided full details of reasons for exclusion in the Characteristics of excluded studies table.
Risk of bias in included studies
No studies met the inclusion criteria.
Effects of interventions
Due to a lack of included studies, we were unable to evaluate the effects of codeine (and derivatives)‐based medications for the treatment of chronic cough in children.
Discussion
Summary of main results
We identified no studies eligible for inclusion in this review, and thus found no evidence to support or oppose the use of codeine or derivatives as antitussive agents for chronic cough in children. Our review process identified paediatric studies that evaluated acute cough, in Bhattacharya 2013, Paul 2004, Shadkam 2010, Taylor 1993, and Yoder 2006, and adult‐specific chronic cough trials (Barroso 1973; Dierckx 1981; Edwards 1977; Matthys 1983, Matthys 1985; Thackray 1978).
Of the paediatric‐specific RCTs that evaluated acute cough (Bhattacharya 2013; Paul 2004; Shadkam 2010; Taylor 1993; Yoder 2006), none reported any statistically significant difference in cough severity between treatment arm and placebo. As the evaluation of safety was an objective of this review, and the authors reported side effects, we have provided a summary of these findings below.
A single‐dose, double‐blind, placebo‐controlled RCT evaluated dextromethorphan, diphenhydramine (an antihistamine) against placebo for the treatment of nocturnal cough due to upper respiratory tract infections in 37 children aged 6 to 18 years (Yoder 2006). The mean cough duration of each treatment arm was 4.17, 3.92, and 4.23 days, respectively. This study found no difference between treatment arms and reported no adverse effects. A similar single‐dose RCT of dextromethorphan, diphenhydramine, and placebo on acute (seven days or less) nocturnal cough in children found that neither drug was superior to placebo in regards to reducing the frequency, severity, and bothersome nature of cough (Paul 2004). More notably, however, this study did report an increased adverse reaction of insomnia in the dextromethorphan arm, but this was not significant (P = 0.07). The design of this study was limited by the inclusion of concurrent antibiotic treatments, common analgesics such as acetaminophen and ibuprofen, administration of a single dose, and the possibility of placebo effect. These findings are consistent with an earlier study by Taylor 1993, who conducted an RCT of 49 children with acute cough (duration of less than 12 days) and found that codeine or dextromethorphan compared to placebo was not more efficacious in reducing cough score and symptom score.
Bhattacharya 2013 conducted a double‐blind RCT of dextromethorphan, promethazine, and placebo in 120 children with acute cough. The study found that when compared to placebo the treatment arms did not confer any greater benefit with respect to symptom scores. The authors also noted that in the entire cohort there was a propensity for the cough to resolve, irrespective of the intervention type (Bhattacharya 2013). The cohort was evenly divided between groups, with 40 children in each arm. Adverse events were higher in children treated with dextromethorphan (32.5%) compared to the placebo group (5%). Adverse events included abdominal pain, nausea, vomiting, drowsiness, and irritability.
In a non‐blind RCT between dextromethorphan, diphenhydramine, honey, and a control group involving 139 children (mean age 37.75 months) with acute cough of 5 days, Shadkam 2010 found honey to be more effective in improving cough frequency, cough severity, and sleep quality when comparing honey with each group separately. However, after each intervention (that is honey, dextromethorphan, and diphenhydramine), the mean difference from baseline was statistically significant. No side effects were reported in the dextromethorphan arm, and in spite of the relative superiority of honey, nervousness was a reported adverse reaction in two children, and the authors further acknowledged the risk associated with honey with regards to botulism in children aged less than 1 year.
The evidence pertaining to acute‐cough management practices was previously evaluated by Smith 2014, who conducted a systematic review of evidence evaluating the antitussive efficacy of over‐the‐counter (OTC) medications in the treatment of acute cough in both adults and children. This review similarly found an overall lack of well‐designed studies and no evidence for or against the efficacy of OTC antitussive medications. The lack of evidence to support codeine and OTC medications for cough in children is further reflected in their absence from expert position statements and international cough guidelines (Berlin 1997; Chang 2006b; Gibson 2010; Gibson 2016; Shields 2008).
An increased awareness of risks associated with codeine has prompted many governmental bodies to review legislation and moderate availability of these drugs, and in recent years there has been an increasing international trend toward greater regulatory framework surrounding the availability and use of codeine in children. Following the American College of Chest Physician's chronic cough guidelines, which recommended against using codeine and OTC medications for cough in children (Chang 2006b), and a citizen petition on the safety and efficacy of OTC cough and cold medications, the US Food and Drug Administration convened an expert advisory committee to evaluate the dispensing practices and accessibility of OTC medications to children (US Food and Drug Administration 2015). More recently, in April 2015 the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency conducted an investigation into the use of codeine‐based medications as antitussive agents. The investigation concluded that there is a lack of sufficient evidence to support the use of codeine as an effective antitussive agent and that there are continued and varied safety concerns associated with this drug. As a result, the PRAC found codeine to be contraindicated in children less than 12 years of age and recommended it not be used. The report further recommended such medications not be used by children aged 12 to 18 years with breathing difficulties; any person known to be an ultra‐rapid metaboliser; or breastfeeding mothers (European Medicines Agency 2015). Principal justification for reform is the unpredictability of codeine to morphine conversion in children and the increased vulnerabilities of children predisposed to airway insufficiency (European Medicines Agency 2015). Similar conclusions pertaining to codeine use were made following investigations by Health Canada (Health Canada 2015), the New Zealand Medicines Adverse Reactions Committee (Medsafe 2015), and the Therapeutic Goods Association of Australia (Therapeutic Goods Administration 2015). Reviews into the continued risks, drug availability, and scheduling classifications are currently under way in the United States, US Food and Drug Administration 2016, and in Australia, where these medications continue to be made available OTC for children aged 6 to 11 years.
Overall completeness and applicability of evidence
This review has highlighted a considerable gap in evidence evaluating codeine (and derivatives) antitussive agents in childhood chronic cough. Identified studies of relevance focused on paediatric populations with acute cough or on adult populations. The pathophysiological differences between adults and children, in addition to the different aetiologies between acute and chronic cough, limit the overall generalisability of these findings.
Quality of the evidence
We found no evidence to support or oppose the use of codeine (or derivatives) for the management of chronic cough in children.
Potential biases in the review process
There were no protocol deviations within this review process, and two review authors independently reviewed the searches using a standardised inclusion/exclusion criteria. We thus believe that there were no potential biases in the determination of studies eligible for inclusion in this review.
Agreements and disagreements with other studies or reviews
Our findings of the absence of any RCTs on the efficacy of codeine and its derivatives for chronic cough, along with its potential serious adverse events including death, are consistent with other prior systematic reviews undertaken in the writing of national and international cough guidelines for children (Chang 2006b; Gibson 2010; Shields 2008). In acute cough, a systematic review found "codeine to be no more effective than placebo" (Smith 2014). This Cochrane review on OTC medications for children and adults concluded that "there is no good evidence for or against the effectiveness of over‐the‐counter cough medicine" (Smith 2014). In adults with chronic cough, a systematic review found codeine and dextromethorphan more beneficial in reducing cough frequency and severity than placebo but, due to a limited number of studies and study design flaws, the authors concluded that "there were insufficient data to draw conclusions about their relative efficacy" (Yancy 2013).
PRISMA study flow diagram.
