Nasal Decongestants for the Common Cold (Protocol)

Cochrane Database of Systematic Reviews

Nasal decongestants for the common cold (Protocol)

Ta’i SH, Ferguson KAM, Singh HK, Sharma AN, Kumar S, van Driel ML, De Sutter AIM

Ta’i SH, Ferguson KAM, Singh HK, Sharma AN, Kumar S, van Driel ML, De Sutter AIM. Nasal decongestants for the common cold. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD009612. DOI: 10.1002/14651858.CD009612. www.cochranelibrary.com

Nasal decongestants for the common cold (Protocol) Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER...... 1 ABSTRACT ...... 1 BACKGROUND ...... 1 OBJECTIVES ...... 2 METHODS ...... 2 ACKNOWLEDGEMENTS ...... 5 REFERENCES ...... 5 CONTRIBUTIONSOFAUTHORS ...... 6 DECLARATIONSOFINTEREST ...... 6

Shayan H Ta’i1, Kylie AM Ferguson1, Harsheel K Singh1, Atul N Sharma1, Shilpa Kumar1, Mieke L van Driel1,2,3, An IM De Sutter 3,4

1Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Australia. 2Discipline of General Practice, School of Medicine, The University of Queensland, Brisbane, Australia. 3Department of General Practice and Primary Health Care, Ghent University, Ghent, Belgium. 4Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium

Contact address: Shayan H Ta’i, Faculty of Health Sciences and Medicine, Bond University, University Drive, Robina, Gold Coast, Queensland, 4229, Australia. [email protected]. [email protected].

Editorial group: Cochrane Acute Respiratory Infections Group. Publication status and date: New, published in Issue 2, 2012.

Citation: Ta’i SH, Ferguson KAM, Singh HK, Sharma AN, Kumar S, van Driel ML, De Sutter AIM. Nasal decongestants for the common cold. Cochrane Database of Systematic Reviews 2012, Issue 2. Art. No.: CD009612. DOI: 10.1002/14651858.CD009612.

ABSTRACT

This is the protocol for a review and there is no abstract. The objectives are as follows:

1. To determine the efﬁcacy of nasal decongestants in the common cold compared with placebo, in children and adults.

2. To identify the possible adverse effects associated with short-term and long-term use of nasal decongestants.

BACKGROUND from school and 20 million absences from work annually, including days missed due to caring for ill children (Pappas 2008). In the United States, there are 25 million visits to the family physician annually due to the common cold and the total economic impact Description of the condition of the common cold in that country reached around USD 40 bil- lion annually (Fendrick 2003). The common cold is viral in nature, afflicts individuals of all Previous reviews have considered the safety and efficacy of thera- ages and often necessitates utilisation of over-the-counter (OTC) and prescription medications and complementary interventions pies for indications including seasonal and perennial allergic rhini- (Simasek 2007). Often caused by the rhinovirus, people typi- tis, chronic rhinitis, common cold and influenza (Dolansky 2008). Many marketed treatments for the common cold exist and consist cally experience rhinorrhoea, sneezing, headache, nasal conges- of multiple active agents with claimed decongestant, anti-secre- tion, cough, fatigue and pharyngitis. In Australia upper respiratory tory and anti-cough actions. tract infections, nasal congestion, pharyngitis and cough consti- Heated, humidified air is one type of treatment intervention. The tute 11% of all consultations in general practice (Fry 1993). Despite the common cold not being a serious condition, it has sub- mechanism behind its use includes its actions to firstly liquefy stantial impact on time lost from work and school, as well as money mucus if dry, thereby allowing it to be cleared more effectively. It also works by the heat of the steam killing the cold virus that may spent on both prescription and OTC medications (Heikkinnenn be present in the mucus. It is not routinely recommended as there 2003). The common cold contributes to 22 million missed days

Nasal decongestants for the common cold (Protocol) 1 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. is insufficient evidence for its use (Singh 2011). OBJECTIVES Analgesics (for example, aspirin, paracetamol and ibuprofen) are also used widely for relief from a range of symptoms experienced 1. To determine the efficacy of nasal decongestants in the with the common cold, such as headache, sore throat, fever and common cold compared with placebo, in children and adults. muscular pain. It is theorised that the prostaglandins that are in- 2. To identify the possible adverse effects associated with hibited by drugs such as ibuprofen cause a reduction in local va- short-term and long-term use of nasal decongestants. sodilation and nasal congestion although there is little reported evidence (Eccles 2009; Eccles 2000). Analgesia administered in OTC doses has a relatively good safely profile. Contra-indications include aspirin in children due to the risk of Reye’s syndrome and METHODS paracetamol in patients who use alcohol in excess (Eccles 2009). Corticosteroids are also used for the treatment of the common cold and are currently being reviewed (Hayward 2009). Intranasal Criteria for considering studies for this review ipratropium bromide has been reviewed and was found to be effective in reducing rhinorrhoea but ineffective in reducing nasal congestion (AlBalawi 2011). Types of studies A Cochrane Review of saline nasal irrigation reported limited ev- Randomised controlled trials (RCTs) and cluster-RCTs compar- idence of efficacy in relieving symptoms from upper respiratory ing nasal decongestants to placebo. We will not include quasi-ran- tract infections (Kassel 2010). domised trials. Combination medications have also been studied. It was reported that combinations of antihistamine, decongestants and analgesics have proved to be more effective compared to placebo (De Sutter Types of participants 2012). Adults and children of all ages and either gender with the common Since these medications for the common cold have already been cold, characterised by defined symptoms of an upper respiratory previously researched, this review will concentrate on nasal decon- tract infection (URTI). We will only include participants who gestants. have had symptoms for no more than seven days prior to the start of the study. We will exclude studies where another upper respiratory condition (such as influenza, sinusitis or rhinitis) has Description of the intervention been diagnosed. Nasal congestion is one of the most uncomfortable symptoms experienced with the common cold (Fry 1993). There is no cure for Types of interventions the common cold, therefore symptomatic therapy is the only treatment option. Nasal decongestants are widely utilised for symp- Oral or topical nasal decongestants versus placebo (oral or spray tomatic relief in both adults and children and can be administered as appropriate). in oral or topical form (Del Mar 2003). We will include trials using topical and oral nasal decongestants administered as aqueous spray, drops, dry powder, tablets or capsules. We will only focus on nasal decongestants, which work by stim- ulating the alpha-adrenergic receptors in upper respiratory tract How the intervention might work blood vessels, leading to vasoconstriction (Wicker 2009). We will Nasal decongestants are sympathomimetic amines that stimulate exclude studies reporting combined interventions such as warm the alpha-adrenergic receptors leading to vasoconstriction in blood humidified air, steam, aromatic vapours, inhaled corticosteroids vessels supplying the upper respiratory tract structures (Wicker and interventions using menthol. We will analyse single-dose and 2009). This results in a net reduction in oedema and nasal secre- multiple-dose studies separately. tions.

Types of outcome measures

Why it is important to do this review The purpose of this systematic review is to study the efﬁcacy and Primary outcomes safety of nasal decongestants in people with a common cold. This 1. Subjective symptom scores for nasal congestion (self review will provide evidence-based guidance to clinicians as well reported scores of congestion). as patients suffering from the common cold. 2. Overall patient well being score (self reported).

Nasal decongestants for the common cold (Protocol) 2 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Secondary outcomes 25 oxymetazoline.tw,nm. 1. Objective measures of nasal airways resistance (NAR). 26 norepinephrine.tw,nm. 2. Adverse events (for example, dry mucous membranes, 27 pseudoephedrine.tw,nm. rebound congestion). 28 phenylephrine.tw,nm. 3. Complications (for example, sinusitis, otitis media, lower 29 xylometazoline.tw,nm. respiratory tract infections). 30 tramazoline.tw. 4. Time to full recovery. 31 Ephedrine/ 5. Time to return to school/work. 32 ephedrin*.tw,nm. 33 or/23-33 34 22 and 34 Search methods for identification of studies Searching other resources We will search www.clinicaltrials.gov and other appropriate trials Electronic searches databases to identify completed and ongoing trials. We will review We will search the Cochrane Central Register of Controlled Clin- reference lists and contact researchers in the field if necessary to ical Trials (CENTRAL) (The Cochrane Library latest issue), which identify further relevant studies. We will contact manufacturers of contains the Cochrane Acute Respiratory Infections (ARI) Group’s nasal decongestants for unpublished studies. Specialised Register, MEDLINE (1950 to present), EMBASE (1974 to present), CINAHL (1982 to present) and LILACS (1985 to present). Data collection and analysis We will use the following search strategy to search MEDLINE and CENTRAL. We will combine the MEDLINE search strategy with the Cochrane Highly Sensitive Search Strategy for identifying Selection of studies randomised trials in MEDLINE (Lefebvre 2011). We will adapt Two review authors (SYK, HS) will independently review and ap- the search strategy for other databases. There will be no language ply the inclusion and exclusion criteria to the titles and abstracts or publication restrictions. identified by the search. We will retrieve the full text if there is 1 Common Cold/ insufficient information in the titles or abstracts to exclude a study. 2 common cold*.tw. One author (SYK) will obtain full texts of the articles. Two review 3 head cold*.tw. authors (SYK, HS) will review full-text articles independently. A 4 coryza.tw. third review author (MLvD) will be consulted if there is any dis- 5 upper respiratory infection*.tw. crepancy between the authors and the issue will be resolved by 6 upper respiratory tract infection*.tw. discussion. The review authors will not be blinded to information 7 (infection* adj3 upper respiratory).tw. about the article, such as the journal title, the authors of the arti- 8 (nasopharyngit* or rhinopharyngit*).tw. cles or the results. 9 nasosinusit*.tw. 10 (acute adj2 (rhinit* or rhinosinusit*)).tw. 11 (rhinorrhoea or rhinorrhoea).tw. Data extraction and management 12 Nasal Obstruction/ Two review authors (ST, AS) will independently extract data from 13 ((nasal or nose*) adj3 (block* or obstruct* or congest* or dis- all included articles using pre-designed data extraction forms. A charge* or runny or running or stuffy or stuffed)).tw. third author (MLvD) will assist in reaching a consensus if data 14 Rhinovirus/ entries differ. 15 rhinovir*.tw. We will extract the following data. 16 Coronavirus Infections/ 1. First author, publication year, journal. 17 coronavirus/ or coronavirus 229e, human/ or coronavirus oc43, 2. Number, age and gender distribution of the patients human/ included in the trial. 18 coronavir*.tw. 3. Case definitions (symptoms and measurements). 19 adenoviridae/ or adenoviruses, human/ 4. Type, dosage, duration and route of administration of nasal 20 Adenovirus Infections, Human/ decongestant. 21 adenovir*.tw. 5. Results (primary and secondary outcomes). 22 or/1-21 6. If a paper does not provide sufficient information regarding 23 exp Nasal Decongestants/ either the details of the study or the results, we will contact the 24 decongestant*.tw,nm. authors where possible.

Nasal decongestants for the common cold (Protocol) 3 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Assessment of risk of bias in included studies of clear face value heterogeneity we will report the outcomes of Two review authors (KF, HS) will independently assess the risk of the studies as in a systematic review but will not pool the results. bias. We will document disagreements and resolve them by dis- If there is no obvious heterogeneity we will use statistical tests 2 2 cussion with an arbiter (MLvD). We will assess: randomisation such as the Cochrane Chi (Q) test and I statistic (Higgins 2003) sequence generation, allocation concealment, blinding of partic- to determine the presence and level of statistical heterogeneity 2 ipants and personnel (if relevant) and outcome assessors, incom- for each outcome. We will consider an I estimate of 60% or plete outcome data, drop-out/selective reporting and other po- more important heterogeneity. Where possible we will explore the tential sources of bias. We will report the risk of bias using the causes of statistical heterogeneity using subgroup and sensitivity Cochrane Handbook for Systematic Reviews of Interventions ’Risk of analyses. We will not carry out a meta-analysis if the heterogeneity bias’ tool (Higgins 2011). is greater than 90% and there is too much variation in the results, particularly inconsistency in the direction of the effect.

Measures of treatment effect Assessment of reporting biases The standard method of measurement of treatment effect will be We will assess reporting bias using funnel plots where we have suf- any symptom score that is used in studies. Subjective symptoms ficient trials (more than 10) and will follow the recommendations can be measured on different scores and as a result we will use sta- on testing for funnel plot asymmetry as described in section 10.4.3 tistical methods to adjust for differences in instruments (standard- of the Cochrane Handbook for Systematic Reviews of Interventions ised mean difference (SMD) to pool data from different scoring (Sterne 2011). systems). We will express dichotomous outcomes as a risk ratio (RR) and report them as odds ratios (OR) that are generated by RevMan Data synthesis software (RevMan 2011). We will calculate 95% confidence in- We will include in the meta-analysis the results from studies that tervals (CIs) for each estimate. meet the inclusion criteria and report any of the selected outcomes. We will express continuous outcomes as mean difference (MD) We will calculate the summary weighted odds ratio (OR) and 95% pre- and post-treatment if measurement is performed using the CI for dichotomous secondary outcomes using the inverse of the same scale. We will express continuous outcomes as SMD to variance of each study result for weighting. We will standardise the achieve a uniform scale if different scales are used across studies. results of the studies to a uniform scale when looking at continuous We will calculate standard deviations (SD) for continuous out- outcomes. We will then use the SMD to express the size of the comes. intervention effect in each study relative to the variability observed in that study. We will calculate the number needed to treat to Unit of analysis issues benefit (NNTB) for an additional beneficial outcome using the summary OR and the average control event rate described in the We will analyse the outcomes of the individual participants of relevant studies. We will perform fixed-effect meta-analyses and each clinical trial. If the unit of randomisation is not the same random-effects meta-analyses and compare the difference between as the level of analysis, i.e. the individual participants, such as in the two models. We will use a random-effects meta-analysis where cluster-randomised trials, then we will make adjustments to take the statistical difference is large. into account the impact of clustering as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Subgroup analysis and investigation of heterogeneity We will carry out a subgroup analysis to explore differential treat- Dealing with missing data ment effects. We will consider the following subgroup analyses. We will contact the trial authors for any missing data. We will carry 1. Children (age 12 or less) versus others (age above 12). out an intention-to-treat (ITT) analysis if we are unable to obtain 2. Topical versus oral nasal decongestants. the information or if it is not available, assuming that all missing data represent unsuccessful outcomes. We will also carry out an on-treatment analysis and compare this with ITT outcomes. Sensitivity analysis We will perform sensitivity analyses to assess the impact of heterogeneity on the overall outcome (pooled estimate) of the meta- Assessment of heterogeneity analysis. We will do this by gradually removing single trials to in- We will assess heterogeneity in two ways. First, we will explore vestigate the extent to which they contribute to heterogeneity. We the presence of heterogeneity at face value by comparing across will also use sensitivity analyses to assess the impact of risk of bias studies’ population groups, interventions or outcomes. In the case on the overall pooled estimate by first pooling the studies with

Nasal decongestants for the common cold (Protocol) 4 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. low risk of bias and then gradually adding the studies assessed as having a high risk of bias.

ACKNOWLEDGEMENTS We wish to thank and acknowledge David Taverner and G. Jenny Latte, review authors of the initial Cochrane Systematic Review on which this protocol is based. We also wish to thank the following for commenting on the draft of this protocol: Ankur Barua, Cheryl Flynn, Ron Eccles, Conor Teljeur and Chris Del Mar.

REFERENCES

Additional references cold. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/14651858.CD008116] AlBalawi 2011 Heikkinnenn 2003 AlBalawi ZH, Othman SS, AlFaleh K. Intranasal Heikkinnenn T, Jarvinen A. The common cold. Lancet ipratropium bromide for the common cold. Cochrane 2003;361(9351):51–9. Database of Systematic Reviews 2011, Issue 7. [DOI: 10.1002/14651858.CD008231.pub2] Higgins 2003 Higgins JP, Thompson SG, Deeks JJ, Altman DG. De Sutter 2012 Measuring inconsistency in meta-analysis. BMJ 2003;327 De Sutter AIM, van Driel ML, Kumar AA, Lesslar O, Skrt (7414):557–60. A, French L. Oral antihistamine-decongestant-analgesic combinations for the common cold. Cochrane Database Higgins 2011 of Systematic Reviews 2012, Issue 1. [DOI: 10.1002/ Higgins JPT, Green S (editors). Cochrane Handbook for 14651858.CD004976.pub2] Systematic Reviews of Interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration. Available from Del Mar 2003 www.cochrane-handbook.org. Chichester: Wiley-Blackwell, Del Mar C, Glasziou P. Upper respiratory tract infection. 2011. BMJ Clinical Evidence 2003;10:1747–56. Kassel 2010 Dolansky 2008 Kassel JC, King D, Spurling GKP.Saline nasal irrigation for Dolansky G, Rieder M. What is the evidence for the acute upper respiratory tract infection. Cochrane Database safety and efficacy of over-the-counter cough and cold of Systematic Reviews 2010, Issue 3. [DOI: 10.1002/ preparations for children younger than six years of age?. 14651858.CD006821.pub2] Journal of Paediatrics and Child Health 2008;13(2):125–7. Lefebvre 2011 Eccles 2000 Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching Eccles R. Pathophysiology of nasal symptoms. American for studies. In: Higgins JPT, Green S editor(s). Cochrane Journal of Rhinology 2000;14(5):335–8. Handbook for Systematic Reviews of Interventions Version Eccles 2009 5.1.0 [updated March 2011]. The Cochrane Collaboration. Eccles R. Over the counter medicines for colds. In: Eccles Available from www.cochrane-handbook.org. Chichester: R, Webber O editor(s). Common cold. Basel: Birkhauser Wiley-Blackwell, 2011. Verlag, 2009:23–45. Pappas 2008 Fendrick 2003 Pappas D, Hendley J, Hayden F, Winther B. Symptom Fendrick AM, Monto AS, Nightengale B, Sarnes M. The profile of common colds in school-aged children. Pediatric economic burden of non-influenza-related viral respiratory Infectious Disease Journal 2008;27:8–11. tract infection in the United States. Archives of Internal RevMan 2011 [Computer program] Medicine 2003;163(4):487-94. The Nordic Cochrane Centre, The Cochrane Collaboration. Fry 1993 Review Manager (RevMan). Version 5.1. Copenhagen: Fry J, Sandler G. Common diseases. Their nature, prevalence The Nordic Cochrane Centre, The Cochrane Collaboration, and care. 5th Edition. Dordrecht: Kluwer Academic, 1993. 2011. Hayward 2009 Simasek 2007 Hayward G, Thompson MJ, Heneghan CJ, Perera R, Del Simasek M, Blandino D. Treatment of the common cold. Mar CB, Glasziou PP. Corticosteroids for the common American Family Physician 2007;75(4):515–20.

Nasal decongestants for the common cold (Protocol) 5 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Singh 2011 Wicker 2009 Singh M, Singh M. Heated, humidiﬁed air for the common Wicker A, Labruzzo B. Recommendations for the cold. Cochrane Database of Systematic Reviews 2011, Issue 5. use of OTC cough and cold medications in children: [DOI: 10.1002/14651858.CD001728.pub4] decongestants. US Pharmacist 2009;34(3):33–6. Sterne 2011 References to other published versions of this review Sterne JAC, Egger M, Moher D. Chapter 10: Addressing reporting biases. In: Higgins JPT, Green S, editors(s). Taverner 2007 Cochrane Handbook for Systematic Reviews of Interventions Taverner D, Latte J. Nasal decongestants for the common Version 5.1.0 [updated March 2011]. The Cochrane cold. Cochrane Database of Systematic Reviews 2007, Issue 1. Collaboration. Available from www.cochrane-handbook.org. [DOI: 10.1002/14651858.CD001953.pub4] Chichester, UK: Wiley-Blackwell, 2011. ∗ Indicates the major publication for the study

CONTRIBUTIONSOFAUTHORS Shayan Tai (ST), Kylie Ferguson (KF), Harsheel Singh (HS), Atul Sharma (AS) and Shilpa Kumar (SK) co-authored the protocol. Mieke van Driel (MVD) and An De Sutter (ADS) guided the methodological process and commented throughout the writing of the protocol.

DECLARATIONSOFINTEREST The review authors have no conﬂicts of interest for this review.