Methods

Study design: RCT

Study duration: 2010 to November 2012

Participants

• Setting: a paediatric outpatient clinic, Shariatee Hospital, Bandar Abbas

• Country: Iran

• Health status: viral upper respiratory tract infection with complaints of sneezing, blocked nose, sore throat, cough, mild headache

• Number: treatment (63); control (63)

• Age (mean ± SD)

  • treatment: 45.21 ± 11.39 months

  • control: 43.98 ± 11.95 months

• Sex (M/F): 60/66

  • treatment (M/F): 27/36

  • control (M/F): 33/30

Exclusion criteria

Onset of otitis or sinusitis symptoms; onset of symptoms of lower respiratory tract involvement; adding a bacterial infection (purulent nasal discharge, high fever, difficulty breathing, periorbital oedema, facial pain); not using recommended treatments; adding other drugs to recommended treatment; conflicting reports of the carers of the participants

Interventions

Treatment group

• Intervention: honey (Mahram)

• Dose, duration, frequency, administration: honey was placed in glasses similar to those belonging to diphenhydramine and with a similar concentration, mixed with distilled lukewarm water, administered 3 times a day, with last dose given an hour before sleeping.

Control group

• Intervention: 5 mg/kg diphenhydramine syrup

• Dose, duration, frequency, administration: 5 mg/kg body weight, 3 times a day, with last dose given an hour before sleeping

Honey was given in the same volume, frequency, and duration of use as diphenhydramine.

Outcomes

• Severity of cough

• Frequency of cough

Notes

• Funding source: unknown

• Contact with study authors for additional information: we contacted authors for additional information but received no response.

• A volunteer translated the study from Farsi to English.

• A 7‐point Likert‐like scale was used for cough assessment.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Not described but likely done. Randomisation was done by the hospital pharmacist who was not involved in the study.

Allocation concealment (selection bias)

Low risk

Not described but probably done. Quote: "The classification of patients was done by the hospital pharmacist"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Honey was placed in glasses similar to those belonging to diphenhydramine and with a similar concentration, mixed with distilled lukewarm water. The honey and diphenhydramine mixtures were prepared by the pharmacist, who was not part of the study. The paediatricians and parents were unaware of the nature of the treatment each child received.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "the treating doctor and the mother were unaware of the nature of the medication (honey or diphenhydramine)"; "In order to prevent the confounding factor of mother’s anxiety or her personal situation, her reports were only accepted if they were corroborated by the reports of a third person close to the child"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All children randomised to treatment arms completed the 2‐day study.

Selective reporting (reporting bias)

Low risk

Both outcomes listed in the methods section were reported.

Other bias

Unclear risk

Results were presented as the proportion of children with reduced symptom cough instead of the actual mean symptom scores. Furthermore, the scale used for measurement was not clear (a 7‐point Likert‐like scale was used for cough assessment). The protocol was registered retrospectively after completion of the study.

Methods

Study design: RCT

Study duration: January 2009 to December 2009

Participants

• Setting: 6 paediatric community clinics

• Country: Israel

• Health status: children with upper respiratory infection who "were ill with a mean ± SD of 2.8 ± 2.0 days before enrolment". Upper respiratory infection was "defined by the presence of cough and rhinorrhea of #7 days’ duration".

• Number (total = 300):

  • treatment 1, eucalyptus honey (N = 75)

  • treatment 2, citrus honey (N = 75)

  • treatment 3, Labiatae honey (N = 75)

  • control, placebo (N = 75)

• Age: median age of children who completed the study was 29 months (range 12 to 71 months).

  • treatment:

    • eucalyptus honey: mean 27.5 months ± 13.9

    • citrus honey: mean age 29 months ± 13.5

    • Labiatae honey: mean age 30 months ± 16.6

  • control: mean age 29 months ± 14.9

• Sex: unclear

Exclusion criteria

Quote: "children were excluded if they had signs or symptoms of asthma, pneumonia, laryngotracheobronchitis, sinusitis, and/or allergic rhinitis. Children were also excluded if they had used any cough or cold medication or honey on the night before entering the study"

Interventions

Treatment group

• Intervention: eucalyptus honey, citrus honey, or Labiatae honey (3 intervention arms)

• Dose, duration, frequency, administration: single 10 g dose administered 30 minutes before bedtime

Control group

• Intervention: silan (date) extract (similar structure, colour, and taste to honey)

• Dose, duration, frequency, administration: single 10 g dose administered 30 minutes before bedtime

Outcomes

• Cough frequency

• Cough severity

• Bothersome nature of cough

• Child and parent sleep quality

• The combined score of these 4 measures

Notes

• Funding source: quote: "Supported in part by a research grant from Israel Ambulatory Paediatric Association, Maternal Infant Nutrition Research Institute and the Honey Board of Israel"

• Contact with study authors for additional information: we contacted the authors to confirm the proportion of boys to girls of the 300 children randomised. Authors did not respond to our query.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was in blocks of 4.

Allocation concealment (selection bias)

Low risk

The envelopes containing the codes for the study preparations were stored at the office of the Ministry of Agriculture, Extension service, Beekeeping Department and were not opened until after the statistical analysis was completed.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

The 3 honeys and the placebo were prepared by someone not involved in the study; interventions were packed in small plastic containers marked A, B, C, and D and distributed to the paediatric community clinics. Silan date extract was used as a placebo because its structure, brown colour, and taste are similar to that of honey. The parents, physicians, and investigators did not know the content of the preparation that was dispensed.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The parents, physicians, and investigators did not know the content of the preparation that was dispensed. Interventions were packed in small plastic containers marked A, B, C, and D and distributed to the paediatric community clinics. Silan date extract was used as a placebo because its structure, brown colour, and taste are similar to that of honey.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

14 (19%), 13 (18%), 2 (3%), and 4 (5%) children were lost to follow‐up in the eucalyptus honey, citrus honey, Labiatae honey, and placebo groups, respectively. The authors stated that the reasons for loss to follow‐up were unknown. However, attrition was significantly high in the eucalyptus honey and citrus honey groups. It is unclear if the reasons for attrition in the treatment groups were related to the study or not and if the reasons were similar.

Selective reporting (reporting bias)

Low risk

All outcomes listed in the protocol were reported.

Other bias

Low risk

Not detected

Methods

RCT

Participants

• Setting: a single outpatient general paediatric practice

• Country: USA

• Health status: "The URIs were characterized by the presence of rhinorrhea and cough for 7 or fewer days’ duration. Other symptoms may have included but were not limited to congestion, fever, sore throat, myalgias, and headache" (p. 1141)

• Number (total = 108):

  • honey (N = 35)

  • control:

    • dextromethorphan (N = 34)

    • no treatment (N = 39)

• Age: 2 to 18 years; median age of the 105 children completing the study was 5.22 years (range 2.22 to 16.92 years)

  • treatment (median ± interquartile range, years): honey = 5.43 ± 3.81

  • control (median ± interquartile range, years):

    • dextromethorphan = 4.42 ± 3.83

    • no treatment = 5.22 ± 4.33

• Sex: unclear

Exclusion criteria

Quote: "patients were excluded if they had signs or symptoms of a more treatable disease (e.g., asthma, pneumonia, laryngotracheobronchitis, sinusitis, allergic rhinitis). They were also ineligible when they had a history of reactive airways disease, asthma, or chronic lung disease or were using a drug known to inhibit the metabolism of dextromethorphan, such as selective serotonin reuptake inhibitors. Subjects were also excluded if on the prior evening they had taken a medication that included an antihistamine or dextromethorphan hydrobromide within 6 hours of bedtime or dextromethorphan polistirex within 12 hours of bedtime on the evening prior to or on the day of enrolment" (p. 1141)

Interventions

Treatment group

• Intervention: buckwheat honey

• Dose, duration, frequency, administration: "For the honey group, the volume of honey dispensed was equivalent to the age‐driven volume dispensed for DM [dextromethorphan]"

Control group

• Intervention: "artificially honey‐flavoured DM [dextromethorphan], (17 mg/5 mL prepared using DM hydrobromide powder [100% pure United States Pharmacopeia grade], artificial honey flavoring, coloring, stevia liquid extract, methocel, and simple syrup [Professional Compounding Centers of America, Houston, Texas])", no treatment = empty syringe

• Dose, duration, frequency, administration: "dosage for DM [dextromethorphan] approximated typical OTC label recommendations, with children aged 2 to 5 years receiving 8.5 mg/dose (1/2 teaspoon), children aged 6 to 11 years receiving 17 mg/dose (1 teaspoon), and children aged 12 to 18 years receiving 34 mg/dose (2 teaspoons). Of note, these concentrations slightly exceed typical OTC products, which contain 15 mg/5 mL, and were the result of the compounding process but may be more likely to achieve a beneficial effect based on our previous analyses"

Parents were instructed that their child’s treatment could be given with a non‐caffeinated beverage and should be administered within 30 minutes of the child going to sleep. Intervention and control were in a 10‐millilitre opaque syringe and kept in brown paper bags.

Outcomes

• Cough frequency

• Cough severity

• Bothersome nature of cough

• Cough impact on sleep quality for child and parent

• The combined score of these 4 measures

Notes

• Funding source: "this study was supported by an unrestricted research grant from the National Honey Board, an industry‐funded agency of the USA Department of Agriculture"

• Contact with study authors for additional information: we contacted the lead author for additional information on the proportion of boys to girls of the 108 children randomised and other missing data. Authors responded that they could not provide the information because they no longer have the data.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Not described but probably done. Quote: "The randomisation sequence was constructed by a statistician not affiliated with the study and was then used by the study coordinators to assign treatment group"

Allocation concealment (selection bias)

Low risk

Not described but probably done. Treatment allocation was concealed in 10‐millilitre opaque syringe and kept in brown paper bags.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

The syringes used for all 3 treatment groups were opaque and placed in a brown paper bag to conceal the treatments from the investigators. The no‐treatment group was not blinded to their treatment, but the honey and dextromethorphan arms were blinded.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Although all participants were given syringes in brown paper bags, the no‐treatment group had empty syringes, which could influence the assessment of the outcome.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

2 children from the no‐treatment group were lost to follow‐up; 1 was withdrawn from the dextromethorphan group because the participant did not take the treatment.

Selective reporting (reporting bias)

Low risk

All outcomes were adequately reported.

Other bias

Low risk

It is unclear whether any of the no‐treatment group revealed to any of the assessors during phone conversations that they were given no treatment. Children lost to follow‐up or withdrawn were not included in the final analysis.

Methods

RCT

Participants

• Setting: a paediatric service of Clinica Amaury Coutinho, linked to Recife City Hall

• Country: Brazil

• Health status: "irritative cough for at least 24 hours, which led to the need for medical consultation, participated in the study. Patients should have acute cough due to viral upper airway infection, thus considered due to the presence of mild fever or fever associated with hyaline or catarrhal rhinorrhea, lasting less than 72 hours, without clinical manifestations of associated bronchospasm"

• Number (total = 60):

  • treatment: honey (N = 29)

  • control: bromelin (N = 31)

• Age: age in years, mean (25 to 75 percentiles):

  • treatment: honey: mean 5.6 years (2.0 to 7.5 years)

  • control: bromelin: mean 5.3 years (3.0 to 7.5 years)

• Sex of children who completed study (M/F):

  • treatment: honey (13/16)

  • control: bromelin (13/18)

Exclusion criteria

Children with history of obstructive pulmonary disease, cystic fibrosis, neuropathies, heart disease, diabetes, or identifiable primary or secondary immunodeficiencies

Interventions

Treatment group

• Intervention: honey

• Dose, duration, frequency, administration: children up to 20 kg received 5 mL; for those weighing > 20 kg, 1 mL was administered for every 5 kg additional weight.

Control group

• Intervention: the combination of honey and Ananas comosus extract HBS19820501 (rich in bromelin) as syrup formulation

• Dose, duration, frequency, administration: children up to 20 kg received 5 mL; for those weighing > 20 kg, 1 mL was administered for every 5 kg additional weight.

Quote: "the quality of the honey was certified in both groups and approved by the regulatory agencies and the National Health Surveillance Agency (Anvisa) for sale; the honey had been recently produced and underwent strict bacteriological control"

Outcomes

• Cough frequency

• Reduction in cough severity

Notes

• Funding source: Hebron Indústrias Químicas

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was carried out according to a table generated in Microsoft Excel.

Allocation concealment (selection bias)

Low risk

Not described but very likely. Treatments were labelled A and B. Quote: "Neither the investigator nor the patient, nor the family knew which product was used"; "The treatment groups were revealed only after the analysis of the study results"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Quote: "neither the investigator nor the patient, nor the family knew which product was used. The treatment groups were revealed only after the analysis of the study results"

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Quote: "neither the investigator nor the patient, nor the family knew which product was used. The treatment groups were revealed only after the analysis of the study results"

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants randomised were included in the final analysis.

Selective reporting (reporting bias)

Low risk

All outcomes listed in the study protocol and methods section were reported.

Other bias

Unclear risk

Used an unvalidated 5‐point cough scale that differed from the cough scale used by the other included studies

Methods

RCT

Participants

• Setting: 6 paediatric community clinics

• Country: Iran

• Health status: "2 to 5 years of age with URTIs, nocturnal symptoms and illness duration of 5 days. All or some of these children were suffering from symptoms such as rhinorrhoea, sneeze, sore throat, and stuffed nose. Their coughing had lasted 5 days"

• Number (total = 160):

  • treatment: honey (N = 40)

  • control:

    • dextromethorphan (N = 40)

    • diphenhydramine (N = 40)

    • no treatment (N = 40)

• Age (children who completed the study): 37.75 ± 11.12 months

  • treatment: honey: mean age 37 ± 11.4 months

  • control:

    • dextromethorphan: mean age 37 ± 11.1 months

    • diphenhydramine: mean age 38 ± 11.4 months

    • no treatment: mean age 37.8 ± 10.9 months

• Sex: not reported

Exclusion criteria

"asthma, pneumonia, laryngotracheobronchitis, sinusitis, allergic rhinitis, chronic lung disease, congenital heart disease, malignancy, and diabetes were not included in the study. antihistamine, diphenhydramine, or dextromethorphan 4 hours before sleep or had consumed cytochrome P450 inhibitors simultaneously (i.e. serotonin‐reabsorption selective inhibitors) were also excluded from the study. Parents were also excluded if they were using a drug and herbal that had an effect on sleeping, such as sedatives"

Interventions

Treatment group

• Intervention: a single dose of natural honey from Kafi‐Abad (a village in Yazd, Iran)

• Dose, duration, frequency, administration: received 2.5 mL of natural honey before sleep

Control group

• Intervention: dextromethorphan, diphenhydramine, or no treatment (received supportive treatment recommended for other groups as well)

• Dose, duration, frequency, administration: the second (dextromethorphan) and third (diphenhydramine) groups received 2.5 mL of dextromethorphan syrup (7.5 mg, Pour‐Sina drug manufacturing company in Tehran, Registered No. 1228051241) and 2.5 mL of diphenhydramine syrup (6.25 mg, RamooFarmon drug manufacturing company, Registered No. 1228056772), respectively, before sleep.

• All treatment arms were advised to take supportive treatment with saline nose drops, water vapour, cleaning of a blocked nose, and use of paracetamol for fever, if necessary. All mothers were offered the same standard on the disease and how to use liquids, nose drops, and humidifier by a paediatrician.

Outcomes

• Cough frequency

• Cough severity

• Child sleep score

• Parents' sleep quality

Notes

• Funding source: Department of Research Administration, Shahid Sadoughi University of Medical Sciences (SSUMS) in Yazd, Iran

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation was by random numbers table.

Allocation concealment (selection bias)

Unclear risk

It was not clear whether treatment allocation was concealed.

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Neither the investigators nor caregivers were blinded to treatments given, which could greatly influence the assessment of outcome.

Blinding of outcome assessment (detection bias)
All outcomes

High risk

Neither the investigators nor caregivers were blinded to treatments given, which could greatly influence the assessment of outcome.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

7 participants from the honey group, 4 from the dextromethorphan group, 6 from the diphenhydramine group, and 4 from the no‐treatment group were either lost to follow‐up or withdrawn for violating the protocol. Attrition was high for the honey and diphenhydramine groups. Participants were excluded from analysis for not visiting the physician as scheduled or using the drugs inappropriately. The proportion of children who did not visit physician as scheduled or violated protocol per group was unclear.

Selective reporting (reporting bias)

Low risk

All outcomes listed in the protocol were reported.

Other bias

Unclear risk

Some of the questions put to mothers were answered by the paediatrician because the questions were ambiguous, which could also have influenced the assessment of outcomes. Since mothers were filling in the questionnaire in the presence of the physician, it is unclear if this could have influenced the assessment of outcomes (p. 788)

Methods

RCT

Participants

• Setting: the paediatric casualty of the Aga Khan University Hospital Nairobi. This is a national tertiary referral and teaching hospital serving the middle‐ and upper‐income society in Nairobi and its environment.

• Country: Kenya

• Health status: an uncomplicated acute upper respiratory infection (authors did not define acute upper respiratory infection)

• Number (total = 145):

  • treatment: honey (N = 57)

  • control:

    • salbutamol (N = 43)

    • placebo (N = 45)

• Age: 1 to 12 years

  • treatment: not clear

  • control: not clear

• Sex of children who completed study (M/F):

  • honey (30/24)

  • control:

    • salbutamol (unclear)

    • placebo: (unclear)

Exclusion criteria

Prior use (48 hours) of any cough mixture, study agents, oral antihistamines, nasal decongestants, steroids, or antibiotics. Other exclusions were any past history of atopy, asthma, or any chronic lung disease as well as hospitalisation for lower respiratory tract infection in the past 6 months.

Interventions

Treatment group

• Intervention: the darkest locally available honey was used.

• Dose, duration, frequency, administration: 2.5 mL (age 1 to 2 years), 5 mL (age 2 to 6 years), 7.5 mL (age 6 to 12 years); all were administered 3 times daily for 5 days

Control group

• Intervention:

  • salbutamol has 2 mg of active ingredient per 5 mL.

  • placebo was a brown‐coloured sugar and alcohol‐free syrup with an inert thickening agent whose ingredients included sodium citrate, citric acid monohydrate hypromellose, sodium benzoate, saccharin sodium, sodium chloride, caramel colour, and water.

• Dose, duration, frequency, administration: 2.5 mL (age 1 to 2 years), 5 mL (age 2 to 6 years), 7.5 mL (age 6 to 12 years); all were administered 3 times daily for 5 days

Outcomes

• Cough frequency

• Cough severity

• Bothersome cough

• Cough effect on children's sleep

• Cough effect on parents' sleep

• Combined symptom score

Notes

• Funding source: Universal Corporation Ltd prepared all study drugs at no cost.

• Contact with study authors for additional information: we contacted the authors for additional information on cough scores and mean age of children randomised.

• It is unclear if the salbutamol was oral or inhaled. It was most likely oral because parents were given all study drugs to administer to their children at home.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Dispensing study drugs was undertaken following a random order previously generated by a statistician not involved in care of study participants.

Allocation concealment (selection bias)

Low risk

Not described, but risk of bias unlikely. All 3 study drugs were prepared, bottled, packaged, and labelled as Study Drug A, B, and C by Universal Corporation Ltd, who also held the code until after statistical analysis was completed.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All 3 study drugs were prepared, bottled, packaged, and labelled as Study Drug A, B, and C by Universal Corporation Ltd, who also held the code until after statistical analysis was completed.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All 3 study drugs were prepared, bottled, packaged, and labelled as Study Drug A, B, and C by Universal Corporation Ltd, who also held the code until after statistical analysis was completed.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

13%, 7%, and 5% of children in the placebo, honey, and salbutamol groups, respectively, were lost to follow‐up or were in violation of study protocol. It is unclear if the reasons for not completing the study were the same across study groups. It is possible that more participants in the placebo group left because their condition worsened.

Selective reporting (reporting bias)

Low risk

Not detected

Other bias

Low risk

Unlikely