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Over-the-counter (OTC) medications to reduce cough as an adjunct to antibiotics for acute pneumonia in children and adults

  1. Christina C Chang1,*,
  2. Allen C Cheng2,
  3. Anne B Chang3

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 10 MAR 2014

Assessed as up-to-date: 22 JAN 2014

DOI: 10.1002/14651858.CD006088.pub4


How to Cite

Chang CC, Cheng AC, Chang AB. Over-the-counter (OTC) medications to reduce cough as an adjunct to antibiotics for acute pneumonia in children and adults. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD006088. DOI: 10.1002/14651858.CD006088.pub4.

Author Information

  1. 1

    The Alfred Hospital, Monash University, Department of Infectious Diseases, Prahran, Victoria, Australia

  2. 2

    2nd Floor, Burnet Centre, Alfred Hospital, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia

  3. 3

    Charles Darwin University, Menzies School of Health Research, Casuarina, Northern Territories, Australia

*Christina C Chang, Department of Infectious Diseases, The Alfred Hospital, Monash University, Commercial Road, Prahran, Victoria, 3181, Australia. christina.chang@monash.edu. christina.chang@med.monash.edu.au ccchang339@hotmail.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 10 MAR 2014

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Characteristics of included studies [ordered by study ID]
Aquilina 2001

MethodsSingle-centre, double-blind, parallel, placebo-controlled RCT. Method of recruitment was not specified
Concomitant antitussives, mucolytics and beta-2 agonist disallowed. Clinical evaluation performed on baseline, days 3, 7 and final. Participants assessed for signs and symptoms relevant to diagnosis of acute or chronic lung disease including sputum volume and characteristics, dyspnoea, cough, pulmonary auscultation, difficulty in expectorating

Compliance not mentioned. Inclusion and exclusion criteria described in next column

Description of withdrawals or drop-outs not mentioned


Participants14 participants allocated to neltenexine, 14 to placebo. 3 within group had pneumonia but data specific to pneumonia were unavailable
Mean age of total group was 57.5 years (SD 3.04)
Inclusion criteria: adults (aged > 18 years) with acute and chronic lung disease
Exclusion criteria: pulmonary tuberculosis, lung cancer, allergy to neltenexine, severe bronchospasm (requiring beta-2 agonist, corticosteroids or aminophylline), or pregnant or lactating women


InterventionsNeltenexine (a mucolytic), 37.4 mg tds or placebo (1 tablet tds) for 10 to 12 days


OutcomesOverall physicians' assessment of efficacy scored: excellent, good, moderate, not satisfactory. Exact quantification unspecified
Sputum volume, sputum characteristics (1 = serous to 5 = very purulent), and 5-point scores for dyspnoea, cough, pulmonary auscultation, difficulty in expectorating, from 0 (absent) to 4 very severe


NotesWrote to authors with no response
Data for pneumonia alone not available


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot specified

Allocation concealment (selection bias)Unclear riskNot specified

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo used

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPlacebo used

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDrop-outs unclear

Selective reporting (reporting bias)Unclear riskData for pneumonia alone could not be extracted

Other biasUnclear riskData for pneumonia alone could not be extracted. Single-centre study; further information sought from trial authors with no response

Azzopardi 1964

MethodsSingle-centre, double-blind, placebo-controlled RCT. Participants recruited from inpatients in the geriatric unit of Barnet General Hospital, England. The method of randomisation and allocation was not described. When the medication (active or placebo) was considered ineffective, the pharmacist was asked to change to alternate treatment. Data card and observation record prepared for each participant, other medications recorded and authors indicated that these factors were taken into account when assessing response to trial drugs (but did not specify how). Inclusion and exclusion criteria not described. Description of withdrawals or drop-outs not mentioned


ParticipantsTotal randomised unknown. Total described in group unclear as some participants could have been counted twice given potential cross-over methodology. If assumed cross-over was undertaken for all, total randomised would be 34
Age of participants not given
Participants had variety of aetiological factors for cough (pneumonia, acute and chronic bronchitis, bronchiectasis, carcinoma, cardiac failure, cor pulmonale, nervous cough, coryza, influenza)

Inclusion and exclusion criteria not described


InterventionsDimyril (active ingredient = isoaminile citrate, a codeine derivative) or placebo in identical bottles. Dose used varied. Initially 3 to 4 times/day followed by 'as necessary' dosing of up to 5 times a day (1 to 2 G)


OutcomesOutcomes not clearly specified

Paper stated: "The evidence of the patient, the several observers (day and night nurses, physician, and medico-social worker), the number of doses per 24 hours, and (when recorded) the actual cough frequencies were considered in deciding whether or not the nuisance and frequency of cough had been reduced"


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not specified

Allocation concealment (selection bias)Unclear riskMethod not specified

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo used and pharmacists not connected to trial involved

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPlacebo used and pharmacists not connected to trial involved

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOutcome of drop-outs and withdrawals unclear

Selective reporting (reporting bias)Unclear riskOutcomes not clearly specified

Other biasUnclear riskInsufficient data to be certain

Principi 1986

MethodsMulti-centre, double-blind, parallel, placebo-controlled RCT. Children recruited from 3 hospitals in Italy

Potential participants admitted into hospital for symptoms of pneumonia screened for inclusion criteria (next row) Double-blinded study and all participants were treated as inpatients and re-evaluated daily for heart rate, respiratory rate and maximal rectal body temperature. Cough, dyspnoea and chest pathological scores also recorded daily. Chest X-ray on admission and end of treatment. Compliance not mentioned but presumed excellent given inpatient study

All children given antibiotics (see column on intervention). Other co-treatment (e.g. anti-pyretic agents) not mentioned
Inclusion and exclusion criteria described in next column

Description of withdrawals or drop-outs not mentioned. As children were inpatients, assumed most followed up. Chest X-ray follow-up rate 115/120 = 95.8%


ParticipantsTotal of 120 children randomised - 60 in each arm. Outcome measure available for 115 children (57 active arm, 58 controls), 95.8%

Antibiotic with ambroxol group: mean age not given, 11 aged < 1 year, 9 aged 1 to 2 years, 19 aged 2 to 5 years, 21 aged 5 to 12 years
Gender: M 28; F 32
Mean body weight: 17.1 kg (SD 1.08)
Antibiotic with placebo: mean age not given, 12 children aged < 1 year, 11 aged 1 to 2 years, 20 aged 2 to 5 years, 17 aged 5 to 12 years
Gender: M 38; F 22
Mean body weight 16.2 kg (SD 1.06)

Inclusion criteria: children admitted into hospital for pneumonia. Have had blood culture performed before commencement of antibiotics and positive for well-defined bacterium or a chest X-ray showing lobar and sub lobar involvement, with erythrocyte sedimentation rate ≥ 30 mm/h and C-reactive protein ≥ 25 μg/mL

Exclusion criteria: taken antibiotics, mucolytics or mucoregulatory drugs in the preceding week


InterventionsTrial medications consisted of ambroxol (1.5 to 2 mg/kg/day in 2 divided doses) or placebo for 10 days. All children also given antibiotics, chosen on basis of microbiological data or in accordance with literature on most probable aetiology for each age, for 7 to 10 days. Children aged < 5 years given oral amoxicillin or intramuscular ampicillin (50 mg/kg in 3 to 4 divided doses). Older children had oral erythromycin ethylsuccinate (50 mg/kg/day in 4 doses)


OutcomesCough, dyspnoea and chest pathological signs scored, ranging from 0 (absent) to 3 (very severe). Chest X-ray findings at the end of treatment were compared to pre-treatment chest X-ray and expressed as normalised, improved or unchanged


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskMethod not specified

Allocation concealment (selection bias)Unclear riskNot mentioned

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo used

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPlacebo used

Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs and withdrawals described

Selective reporting (reporting bias)Low riskFollow-up of > 90% of participants

Other biasUnclear riskInsufficient data to be certain

Roa 1995

MethodsMulti-centre, double-blind, parallel RCT comparing amoxicillin plus bromhexine versus amoxycillin alone. Participants recruited from 22 centres involving internalists or pulmonologists in the Philippines

Potential participants evaluated for inclusion criteria by history, examination, CXR, laboratory tests (blood counts, sputum). The method of randomisation and allocation was not described. Double-blinded study and all participants were treated as outpatients and re-evaluated on days 3, 5, 7 and 10. Compliance monitored by pill counting

Participants allowed to receive medications for fever and constitutional symptoms but not any other cough expectorants or antimicrobials. Inclusion and exclusion criteria described in next column

Description of withdrawals or drop-outs mentioned for entire group. Maximum follow-up rate 375/407 = 92% but less for other aspects


ParticipantsTotal of 407 participants randomised - 201 in active treatment and 206 in control group. 392 completed study (192 active, 200 controls). Compliance of 80% in active group and 85% in control group

Amoxicillin with bromhexine group: mean age 32 (SD 13) years, gender - 117 M: 75 F; 51 with pneumonia, 141 with bronchitis
Amoxicillin alone: mean age 32 (SD 12), gender - 130 M: 70 F; 50 with pneumonia, 150 with bronchitis

Inclusion criteria: adolescents and adults aged 15 to 60 years with uncomplicated community-acquired lower respiratory tract infection (pneumonia or bronchitis), clinically assessed to be bacterial in aetiology. Pneumonia defined as presence of cough < 2 weeks, purulent phlegm, fever and/or leucocytosis (> 10,000 mm3) and pulmonary infiltrates on CXR. Acute bronchitis defined as presence of cough < 2 weeks, purulent phlegm, fever and/or leucocytosis (> 10,000 mm3). Sputum culture had to be sensitive to amoxicillin or if organism resistant, participant included if clinical response at Day 3 occurred on amoxicillin.

Exclusion criteria: frank respiratory failure, coexistent chronic disease (diabetes, renal failure, liver or renal impairment, terminal illness such as cancer, active tuberculosis, healed tuberculosis with bronchiectasis, chronic bronchitis or emphysema, heavy smokers (undefined)), pregnant or lactating, hypersensitivity to study drugs, or recent (< 2 weeks) treatment with antibiotics


InterventionsActive Rx = amoxicillin 240 mg and bromhexine 8 mg, both 4 times/day for 7 days

Control group: amoxicillin alone, 250 mg 4 times/day for 7 days


OutcomesDays 3, 5, 7 and 10. Participants evaluated for clinical response, bacteriological response, subjective symptom scores, adverse events, compliance, complete blood count

Clinical response:
Cured = complete disappearance of pre-treatment symptoms and signs
Improvement = pre-treatment symptoms and signs improved but not cured
Failure = pre-treatment symptoms and signs did not improve or worsened
Indeterminate = clinical response could not be determined

Clinical symptoms:
10 mm visual analogue scale of symptoms of cough frequency, cough discomfort, difficulty breathing not related to cough, chest pain not related to cough, ease of expectoration

Bacteriologic response:
Eradication = absence of pre-treatment pathogen or no more culturable material could be expectorated
Persistence = presence of pre-treatment pathogen
Super-infection = appearance of resistant pathogen after starting treatment
Indeterminate = bacteriologic response could not be reliably assessed


NotesWrote to authors with no response
Data for pneumonia alone available only for global clinical response outcome


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskData not provided

Allocation concealment (selection bias)Unclear riskNot mentioned

Blinding of participants and personnel (performance bias)
All outcomes
Low riskPlacebo used

Blinding of outcome assessment (detection bias)
All outcomes
Low riskPlacebo used

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFollow-up in > 90% for some outcomes but less in others

Selective reporting (reporting bias)Low riskOutcomes of withdrawals and drop-outs mentioned

Other biasLow riskInsufficient data to be certain but multi-centre study from 22 centres, thus likely low

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Aliprandi 2004Non-placebo trial. Study involves comparing levodropropizine, codeine and cloperastine to levocloperastine

Balli 2007Erdosteine is not legally available as an over-the-counter medication in countries such as Australia, the UK and USA. Study compared amoxicillin plus erdosteine to amoxicillin-placebo in children with acute lower respiratory tract infections

Barberi 1993Non-placebo study comparing nimesulide to lysine-aspirin in children

Bartolucci 1981Non-controlled study in 40 adults using anti-phlogistic-balsamic compound (in Italian)

Basnet 2012RCT on zinc as adjunct treatment. No data specific to cough as an outcome measure

Caporalini 2001Non-placebo study comparing neltenexine against N-acetylcysteine

Dotti 1970Randomised controlled study but participants did not have pneumonia (in Italian)

Finiguerra 1981A double-blind study in adults with acute and chronic bronchitis (not pneumonia)

Forssell 1966Non-placebo study comparing drops to syrup formulation of an antitussive in infants and young children (in German)

Hargrave 1975Study examined role of bromhexine in prevention of postoperative pneumonia

Ida 1997A review article describing 3 studies on dimemorfan, a dextromethorphan analogue. Of the 3 cited studies, one was a placebo-controlled trial. Insufficient details were included in the text and further data were not available from the author, who could not be contacted

Jayaram 2000Non-placebo study comparing 2 cough formulations

Mancini 1996The paper summarises 3 studies which were not referenced. The first of the 3 studies described a RCT in children with "acute lower respiratory affections (e.g. acute bronchitis, bronchoalveolitis)". Unknown if children with pneumonia included and results stated reduction in cough scores with no specific data given. We wrote to authors and no response was received

The other 2 studies described were in adults with '"superinfected chronic bronchitis" and "hypersecretory chronic obstructive bronchopneumopathies"

Pelucco 1981Non-randomised, non-placebo study in 26 adults (in Italian)

Titti 2000Erdosteine is not legally available as an over-the-counter medication in countries such as Australia, the UK and USA. Multi-centre RCT compared ampicillin plus erdosteine to ampicillin-placebo in children with acute lower respiratory tract infections

Turrisi 1984Non-randomised, non-placebo study using fenspiride in 20 adults (in Italian)

Wang 2005Study used Fuxiong plaster (i.e. not an OTC medication). Randomised controlled study in children with pneumonia

Wieser 1973Placebo but non-randomised study comparing placebo to prenodiazine in 84 adults (in German)

Zhang 2005Study used Toubiao Qingfei (an externally applied therapy, i.e. not an OTC medication). Randomised controlled study in children with fever from pneumonia

Zurcher 1966Non-placebo, double-blind study comparing Sinecod-Hommel to a codeine-based antitussive in 95 adults (in German)

 
Comparison 1. Children - global assessment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Not cured or not improved1120Odds Ratio (M-H, Fixed, 95% CI)0.40 [0.10, 1.62]

 2 Not improved1120Odds Ratio (M-H, Fixed, 95% CI)0.40 [0.10, 1.62]

 3 Not cured1120Odds Ratio (M-H, Fixed, 95% CI)0.36 [0.16, 0.77]

 
Comparison 2. Children - secondary outcomes

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mean cough score at day 31120Mean Difference (IV, Fixed, 95% CI)-0.25 [-0.33, -0.17]

 2 Mean score at day 101120Mean Difference (IV, Fixed, 95% CI)-0.15 [-0.17, -0.13]

 3 Adverse events (no. of people)1Odds Ratio (M-H, Fixed, 95% CI)Subtotals only

 
Comparison 3. Adults - global assessment

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Not cured or not improved1101Odds Ratio (M-H, Fixed, 95% CI)1.21 [0.48, 3.04]

 2 Not improved1101Odds Ratio (M-H, Fixed, 95% CI)1.21 [0.48, 3.04]

 3 Not cured1101Odds Ratio (M-H, Fixed, 95% CI)0.32 [0.13, 0.75]

 
Comparison 4. Combined children and adults

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Not cured or not improved2221Odds Ratio (M-H, Fixed, 95% CI)0.85 [0.40, 1.80]

 2 Not improved2221Odds Ratio (M-H, Fixed, 95% CI)0.80 [0.38, 1.67]

 3 Not cured2221Odds Ratio (M-H, Fixed, 95% CI)0.34 [0.19, 0.60]

 4 Adverse events (no. of people)2221Odds Ratio (M-H, Fixed, 95% CI)1.2 [0.34, 4.22]

 
Summary of findings for the main comparison.

Mucolytics as an adjunct to antibiotics to reduce cough in acute pneumonia in children and adults

Patient or population: children and adults with acute pneumonia

Settings: any
Intervention: mucolytics (and antibiotics)1

Comparison: antibiotics

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboMucolytics

Number of people who had not improved or had not been cured
(follow-up: 7 to 10 days)
16 per 10014 per 100
(7 to 26)
OR 0.85
(0.4 to 1.8)
221
(2)
⊕⊕⊝⊝
low2,5
Fewer people represents a benefit

Cough score
Scale from: 0 (absent) to 3 (very severe)
(follow-up: 3 days)
The mean cough score in the control groups was
1.45
The mean cough score in the intervention groups was
0.25 lower
(0.33 to 0.17 lower)
120
(1)
⊕⊕⊝⊝
low2,3,4
Data for children only

Adverse events
(follow-up: 10 days)
See commentSee commentNot estimable120
(1)
See comment1 study in children provided data specific to participants with pneumonia - there were no adverse events

Complications (e.g. medication change)See commentSee commentNot estimable0
(0)
See commentComplications were not measured in the trials

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; OR: odds ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1In addition to antibiotics, people with pneumonia often use over-the-counter (OTC) cough medications when at home or request OTC cough medications when in hospital to suppress an annoying cough. There is a question as to whether suppressing cough may prolong pneumonia. Over-the-counter cough medications can include antitussives, expectorants, antihistamine-decongestants, antihistamines and mucolytics (such as bromhexine, ambroxol and neltenexine).
2Allocation concealment unclear.
3Scale not validated.
4Sparse data.
5Sparse data; confidence interval does not rule out the potential for 'more people' not improved or cured with mucolytics.