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Zinc for the common cold

  1. Meenu Singh1,*,
  2. Rashmi R Das2

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 18 JUN 2013

Assessed as up-to-date: 18 JAN 2013

DOI: 10.1002/14651858.CD001364.pub4


How to Cite

Singh M, Das RR. Zinc for the common cold. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD001364. DOI: 10.1002/14651858.CD001364.pub4.

Author Information

  1. 1

    Post Graduate Institute of Medical Education and Research, Department of Pediatrics, Chandigarh, India

  2. 2

    All India Institute of Medical Sciences (AIIMS), Department of Pediatrics, Bhubaneswar, Odisha, India

*Meenu Singh, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Sector 12, Chandigarh, 160012, India. meenusingh4@gmail.com. meenusingh@rediffmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions), comment added to review
  2. Published Online: 18 JUN 2013

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Characteristics of included studies [ordered by study ID]
Al-Nakib 1987

MethodsDouble-blind, placebo-controlled randomised trial


ParticipantsHealthy adults 18 to 50 years


InterventionsTherapeutic trial: participants took 1 lozenge 2-hourly for 6 days
Intervention group: zinc gluconate lozenges containing 23 mg zinc
Placebo group: not stated

Prophylactic trial: participants took 1 lozenge/2 waking hours for a total of 12 lozenges/day for 4.5 days. On the second day they were challenged with HRV-2
Intervention group: zinc gluconate lozenges containing 23 mg zinc
Placebo group: not stated


OutcomesSeverity of symptoms
Mean daily nasal secretions
Total tissue counts
Viral shedding
Biochemical and haematological parameters
Trial 1: urinary zinc levels


NotesAlthough adults were stated to be healthy, no exclusion criteria were stated


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot described. Participants divided into groups balanced by age and sex

Allocation concealment (selection bias)Unclear riskThe method of concealment was not described in detail to allow a definite judgement

Blinding (performance bias and detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of ‘low risk’ or ‘high risk’ of bias

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were no drop-outs or withdrawals

Selective reporting (reporting bias)High risk1 or more outcomes of interest in the review were insufficiently reported so that they could not be entered in a meta-analysis

Other biasUnclear riskThe zinc and placebo lozenges were gifted by RBS Pharma, Milan

Douglas 1987

MethodsDouble-blind, placebo-controlled randomised trial


ParticipantsParticipants in the trial were healthy adults who had in the previous year participated in a study of interferon prophylaxis against rhinovirus infection


InterventionsParticipants took 6 to 8 lozenges/day at 2nd-hourly intervals for a minimum of 3 days and maximum of 6 days if symptoms persisted. New course commenced after 2 weeks if symptoms persisted but type of treatment may differ. Consequently 33 zinc courses and 30 placebo courses
Treatment group: zinc acetate lozenges containing 10 mg zinc
Placebo group: lozenges contained sodium acetate


OutcomesDuration and severity of symptoms (nasal, throat or cough)
Viral cultures


NotesThe duration of the common cold was ≤ 2 days before starting treatment for 56 of the 58 participants. 2 zinc and 5 placebo treatment courses were excluded because lozenges had not been used for ≥ 3 days and at the rate of ≥ 4 per day. The SD value was not reported and was calculated from P value. The zinc lozenges contained high amount of tartrate; as a result zinc dissociates from acetate and binds instantly to tartrate


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskUsed sequentially numbered bottles

Allocation concealment (selection bias)Low riskUsed blocked randomisation in blocks of 4. The code was broken twice (once in middle of study and then at the end of study)

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants and key study personnel ensured. It was unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskPlausible effect size (difference in means) amongst missing outcomes was insufficient to have a clinically relevant impact on observed effect size

Selective reporting (reporting bias)Low riskThe study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way

Other biasUnclear riskThe zinc and placebo lozenges were provided by Fauldings Ltd

Farr 1987a

MethodsDouble-blind, placebo-controlled trial


ParticipantsHealthy adults


InterventionsTrial 1: treatment consisted of initial loading dose of 2 lozenges 36 hours following inoculation with HRV-39, and thereafter 1 lozenge every 2 hours for a total of 8 lozenges/day for 5 days
Intervention group: zinc gluconate lozenges containing 23 mg zinc
Placebo group: lozenges contained 0.00125 mg denatonium benzoate

Trial 2: treatment consisted of initial loading dose of 2 lozenges 2 hours following inoculation with HRV-13, and thereafter 1 lozenge every 2 hrs for a total of 8 lozenges/day for 7 days
Intervention group: zinc gluconate lozenges containing 23 mg zinc
Placebo group: 0.0025 mg denatonium benzoate


OutcomesSeverity and duration of symptoms
Tissue counts
Laboratory tests
Infection rates


NotesExclusion criteria were symptoms of any respiratory illness in the week before the study, a history of hay fever, any familiarity with the taste of either denatonium benzoate or zinc, a history of any chronic disease, pregnancy, lactation or an unacceptable contraceptive method in women of child-bearing potential, and known abuse of habit-forming drugs


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer randomisation

Allocation concealment (selection bias)Low riskEach lozenge was wrapped in cellophane and packaged in an opaque polyethylene bottle bearing the study number, the participants' number, the treatment day and dosing instructions

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data

Selective reporting (reporting bias)Low riskThe study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way

Other biasUnclear riskPartly funded by Bristol Myers Products, Hillside, NJ

Godfrey 1992

MethodsDouble-blind, placebo-controlled randomised trial


ParticipantsParticipants were recruited from among Dartmouth College students and staff who spontaneously presented to the cold clinic at the College Health Service. Age ranged from 18 to 40 years. Inclusion required that the cold had lasted ≤ 2 days. Exclusion criteria were positive bacteriological throat culture, pregnancy, lactation and diabetes mellitus


InterventionsParticipants took 1 lozenge every 2 hours for up to 8 hours a day
Treatment group: zinc gluconate lozenges containing 23.7 mg zinc. Placebo group: lozenges contained tannic acid, glycine and calcium saccharinate in an orange-flavoured, boiled candy base


OutcomesFrequency and severity of symptoms over 7 days


NotesThe mean duration of the common cold was 1.3 days at entry. 8 zinc and 6 placebo participants withdrew from the trial. The SD value was not reported and was calculated from t-value. The zinc lozenge contained glycine, which binds zinc tightly and therefore the free zinc ion level probably was much lower than suggested by the total zinc dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandom numbers table

Allocation concealment (selection bias)Low riskA pharmacist, using a randomisation table provided by the study statistician, packaged containers for individual participants with lozenges according to the production run number and subject identification number

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskPlausible effect size (difference in means) amongst missing outcomes was insufficient to have a clinically relevant impact on observed effect size

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasUnclear riskThe study was sponsored by Godfrey Science and Design, PA and by a grant from the Rorer Pharmaceutical corporation, PA, USA

Kurugol 2006a

MethodsDouble-blind, placebo-controlled trial


ParticipantsThe study was conducted at Ege University Nursery and Primary School including children aged 2 to 10 years. Children with chronic disease, immunodeficiency disorder, asthma and history of hypersensitivity were excluded


InterventionsTherapeutic trial: children received syrup preparation of zinc twice daily for 10 days
Intervention group: zinc syrup consisted of 1.32 g zinc sulphate in 100 cm3 (15 mg of zinc in a 5 cm3 spoonful) and glycerin, glucose, sunset yellow, orange essence, nipajin
Placebo group: similar to above, but lacking the zinc component


OutcomesDuration and severity of cold symptoms


NotesUsed zinc sulfate syrup. A total of 6 (3%) subjects discontinued, 4 for non-compliance and 2 for adverse effects due to medication


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer random numbers generator

Allocation concealment (selection bias)Low riskA statistical consultant programmed a computer-generated randomisation code and prepared the packages of medication

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasLow riskBerko Ilac Company, Turkey, supplied the active and placebo medications and digital thermometers. The company did not participate in designing the study, collecting and analysing the data, or in writing the report

Kurugol 2006b

MethodsDouble-blind, placebo-controlled trial


ParticipantsThe study was conducted at Ege University Nursery and Primary School including children aged 2 to 10 years. Children with chronic disease, immunodeficiency disorder, asthma and history of hypersensitivity were excluded


InterventionsProphylactic trial: children received syrup preparation of zinc once daily for 7 months.
Intervention group: zinc syrup consisted of 1.32 g zinc sulphate in 100 cm3 (15 mg of zinc in a 5 cm3 spoonful) and glycerin, glucose, sunset yellow, orange essence, nipajin
Placebo group: similar to above, but lacking the zinc component


OutcomesNumber of colds per study child
Cold-related school absence
Concomitant antibiotic use


NotesUsed zinc sulfate syrup. A total of 6 (3%) participants discontinued, 4 for non-compliance and 2 for adverse effects due to medication


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer random numbers generator

Allocation concealment (selection bias)Low riskA statistical consultant programmed a computer-generated randomisation code and prepared the packages of medication

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasLow riskBerko Ilac Company, Turkey, supplied the active and placebo medications and digital thermometers. The company did not participate in designing the study, collecting and analysing the data, or in writing the report

Kurugol 2007

MethodsDouble-blind, placebo-controlled trial


ParticipantsThe study was conducted at Ege University Nursery and Primary School including children aged 1 to 10 years. The children who developed symptoms of common cold within the first 24 to 48 hours were registered in the study. Exclusion criteria were common cold symptoms for > 48 hours, immunodeficiency disorder, chronic disease, recent acute respiratory disease (diagnosed by a physician in the previous 2 weeks), zinc allergy, allergic disease or non-allergic rhinitis, positive culture for group A Streptococcus and a positive cell culture for influenza A or B viruses


InterventionsParticipants were asked to take 1 spoonful of syrup twice a day for 10 days
Treatment group: zinc syrup consisted of 1.32 g of zinc sulfate in 100 ml (15 mg of zinc in 5 ml spoonful) and glycerin, glucose, sunset yellow, orange essence and nipajin as preservative
Placebo group: identical to above, but lacking the zinc component


OutcomesDuration and severity of cold symptoms


NotesUsed zinc sulfate syrup. 9 children (3 in the zinc group and 6 in the placebo group) dropped out during the study period because of using antibiotics, decongestants or cough medicine


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer random numbers generator

Allocation concealment (selection bias)Low riskA statistical consultant programmed a computer-generated randomisation code and prepared the packages of medication. The packages were identical in appearance except for the randomisation numbers. The packages were randomly distributed by the study nurse

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasLow riskMedications (active and placebo) and digital thermometers were supplied by Berko Ilaç, Turkey. The company did not participate in designing the study, collecting and analysing the data, or in writing the report

Macknin 1998

MethodsDouble-masked, placebo-controlled trial


ParticipantsStudents were recruited from 2 school districts in Cleveland, Ohio. They were aged 6 to 16 years in grades 1 through to 12. Inclusion required that the cold had lasted for ≤ 24 hours. Participants were excluded if they had an oral temperature greater than 37.7ºC, had previously taken the zinc preparation, were pregnant, had a known immune deficiency, any acute illness other than common cold (e.g. pneumonia, gastroenteritis) or cold symptoms lasting more than 24 hours


InterventionsStudents asked to take zinc lozenges, 10 mg, orally dissolved, 5 times a day (in grades 1 to 6) or 6 times a day (in grades 7 to 12) until their cold symptoms had been completely resolved for 6 hours
Treatment group: zinc gluconate lozenges containing 10 mg zinc in a 3.75 g hard candy that also contained sucrose, corn syrup, glycine
Placebo group: lozenges contained calcium lactate pentahydrate instead of zinc and had similar composition as above


OutcomesDuration of resolution and severity of symptoms


NotesThe median percentage of prescribed lozenges taken was 82.5% in the zinc group. 2 students (1 in each group) provided false information at entry and were excluded from analysis. Mean and SD were not reported and were estimated from the figure. The zinc lozenge contained glycine, which binds zinc tightly and therefore the free zinc ion level probably was lower than suggested by the total zinc dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer random number generator

Allocation concealment (selection bias)Low riskA computer-generated randomisation code was provided to the pharmacist, who held the code and prepared the packages of medication

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of key study participants and personnel attempted, but likely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasUnclear riskThe study was supported by a grant from the Quigley Corporation, Doylestown, Pa

Mossad 1996

MethodsDouble-blind, placebo-controlled trial


ParticipantsParticipants were recruited from among the Cleveland Clinic staff through announcements in internal clinic publications and by word of mouth. They were older than 18 years of age. Inclusion required that the cold had lasted for ≤ 24 hours. Exclusion criteria were pregnancy, immune deficiency or symptoms of the common cold for > 24 hours prior to interview


InterventionsParticipants took 1 lozenge 2-hourly for every waking hour
Treatment group: zinc gluconate lozenges containing 13.3 mg zinc
Placebo group: lozenges contained 5% calcium lactate


OutcomesDuration and severity of cold symptoms


NotesParticipants were assessed for non-adherence to treatment; reasons for non-adherence were: participants had taken antibiotics, condition diagnosed by physician to be other than the common cold, participants filled in diaries from memory, or insufficient lozenges were taken (i.e. fewer than 4 per day for the first 4 days). One participant in the zinc group withdrew from the study on the first day because she could not tolerate the lozenges. Mean and SD were not reported and were estimated from the figure. The zinc lozenge contained glycine, which binds zinc tightly and therefore the free zinc ion level probably was lower than suggested by the total zinc dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer random numbers generator

Allocation concealment (selection bias)Low riskA statistical consultant prepared a computer-generated randomisation code and the packages of medication

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasLow riskThe study was supported by grants from the General Pediatrics Research Fund and the Departments of Infectious Diseases and General Pediatrics of the Cleveland Clinic Foundation

Petrus 1998

MethodsDouble-blind, placebo-controlled trial


ParticipantsParticipants were recruited from the campus of the University of Texas through posted announcements. They were 18 to 54 years of age. Participants were excluded if they had a serious illnesses, organ transplants or disability (including HIV infection)


InterventionsParticipants were instructed to use a lozenge every 1.5 hours while awake during day 0, then 1 lozenge every 2 hours while awake on following days while symptoms were present for 14 days or 6 hours after disappearance of last symptoms
Treatment group: zinc acetate lozenges containing 9 mg zinc in a 2.7 g dextrose base
Placebo group: lozenges contained sucrose octaacetate (0.169 mg)


OutcomesDuration and severity of symptoms


NotesOne subject was lost to follow-up


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot described

Allocation concealment (selection bias)Unclear riskThe method of concealment is not described or not described in sufficient detail to allow a definite judgement

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasUnclear riskFunded by Weider Nutrition International, Salt Lake City, Utah

Prasad 2000

MethodsDouble-blind, placebo-controlled trial


ParticipantsParticipants were students, staff and employees at Wayne State University, Michigan, who were ≥ 18 years. Inclusion required that the cold had lasted for ≤ 24 hours. Exclusion criteria were pregnancy, underlying immunodeficiency, chronic illness, symptoms of common cold for more than 24 hours, or had previously used zinc lozenges to treat common cold


InterventionsParticipants were asked to use 1 lozenge every 2 to 3 hours while awake for as long as they had symptoms
Treatment group: zinc acetate lozenges containing 12.8 mg zinc
Placebo group: lozenges contained 0.25 mg of sucrose octaacetate, 6 mg of peppermint oil, 16 mg silica gel, 3877.75 mg dextrose DC and 100 mg glycerol monostearate


OutcomesDuration of symptoms
Plasma levels of zinc and pro inflammatory cytokines


NotesTwo participants in the placebo group dropped out on day 2


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskUsed randomisation code

Allocation concealment (selection bias)Low riskA research consultant prepared the randomisation code and the packages of medication

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasLow riskFunded partly by George and Patsy Eby Research Foundation. The research foundation had no role in the collection, analysis or interpretation of the data, or in the decision to publish the study

Prasad 2008

MethodsDouble-blind, placebo-controlled trial


ParticipantsParticipants were students, staff and employees at Wayne State University, Michigan, who were ≥ 18 years. Inclusion required that the cold had lasted for ≤ 24 hours. Exclusion criteria were pregnancy, underlying immunodeficiency, chronic illness, symptoms of common cold for more than 24 hours, or had previously used zinc lozenges to treat common cold


InterventionsParticipants were asked to use 1 lozenge every 2 to 3 hours while awake for as long as they had symptoms
Treatment group: zinc acetate lozenges containing 13.3 mg zinc in a hard candy that contained 3.8 g of sucrose and corn syrup
Placebo group: lozenges contained 0.25 mg of sucrose octaacetate


OutcomesDuration of symptoms
Plasma levels of zinc and pro inflammatory cytokines


NotesNo loss to follow-up


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskUsed randomisation code

Allocation concealment (selection bias)Low riskA research consultant prepared the randomisation code and the packages of medication

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasLow riskFunded by National Institutes of Health; George and Patsy Eby Foundation, Austin, Texas (unrestricted research funds to Wayne State University for partial support)

Smith 1989

MethodsDouble-blind, placebo-controlled trial


ParticipantsParticipants were recruited from students from 3 colleges and from 1 family practice. They were older than 18 years. Participants were excluded if they had a serious acute or chronic medical condition, seasonal allergies, productive cough, required antibiotic therapy or had taken any treatment for symptoms within 8 hours of baseline assessment


InterventionsParticipants took a loading dose of 4 lozenges then took 2 every 2 hours for 7 days or 24 hours after disappearance of last symptoms
Treatment group: zinc gluconate lozenges containing 11.5 mg zinc
Placebo group: lozenges contained sucrose octaacetate


OutcomesDuration and severity of symptoms


NotesSixty-four subjects were excluded because of insufficient dose (< 10 lozenges on any day) or insufficient duration of therapy, and 2 were lost to follow-up. Mean and SD were not reported and were estimated from the figure


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskInsufficient information about the sequence generation process to permit judgement of ‘low risk’ or ‘high risk’

Allocation concealment (selection bias)Unclear riskThe method of concealment is not described in sufficient detail to allow a definite judgement

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
High riskThe effect size among missing outcomes enough to induce clinically relevant bias in observed effect size

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasUnclear riskThe study was supported by a grant from McNeil Consumer Products Company

Turner 2000a

MethodsDouble-blind, placebo-controlled trial


ParticipantsParticipants were recruited at 4 different study sites: IMTCI (Lenexa, KS), GFI Pharmaceutical Services (Evansville, IN), TKL Research (Paramus, NJ) and Research Across America (RAA; Dallas). They were 18 to 65 years of age
Inclusion required that the cold had lasted for ≤ 1 calendar day (effectively < 36 hrs). Exclusions not described


InterventionsParticipants took the lozenges every 2 to 3 hours (a total of 6 per day) while awake until cold symptoms resolved
Treatment group: zinc gluconate lozenges containing 13.3 mg zinc
Placebo group: lozenges contained tannic acid, sucrose octaacetate, quinine


OutcomesDuration and severity of symptoms


NotesLoss to follow-up not described. Analysis was based on intention-to-treat principle. Mean and SD were not reported and were estimated from the figure. The zinc gluconate lozenge contained glycine, which effectively binds to zinc and therefore the free zinc ion level probably was lower than suggested by the total zinc dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskUsed drug randomisation code

Allocation concealment (selection bias)Unclear riskThe method of concealment is not described in sufficient detail to allow a definite judgement

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up not described

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasUnclear riskInsufficient information to assess whether an important risk of bias exists

Turner 2000b

MethodsDouble-blind, placebo-controlled trial


ParticipantsParticipants were recruited from 4 different study sites: IMTCI (Lenexa, KS), GFI Pharmaceutical Services (Evansville, IN), TKL Research (Paramus, NJ) and Research Across America (RAA; Dallas). They were 18 to 65 years of age
Inclusion required that the cold had lasted for ≤ 1 calendar day (effectively < 36 hrs). Exclusions not described


InterventionsParticipants took the lozenges every 2 to 3 hours (a total of 6 per day) while awake until cold symptoms resolved
Treatment group: zinc gluconate lozenges containing 11.5 mg zinc
Placebo group: lozenges contained tannic acid, sucrose octaacetate, quinine


OutcomesDuration and severity of symptoms


NotesLoss to follow-up not described. Analysis was based on intention-to-treat principle. Mean and SD were not reported and were estimated from the figure. The zinc gluconate lozenge contained glycine, which effectively binds to zinc and therefore the free zinc ion level probably was lower than suggested by the total zinc dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskUsed drug randomisation code

Allocation concealment (selection bias)Unclear riskThe method of concealment is not described in sufficient detail to allow a definite judgement

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up not described

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasUnclear riskInsufficient information to assess whether an important risk of bias exists

Turner 2000c

MethodsDouble-blind, placebo-controlled trial


ParticipantsParticipants were recruited from 4 different study sites: IMTCI (Lenexa, KS), GFI Pharmaceutical Services (Evansville, IN), TKL Research (Paramus, NJ) and Research Across America (RAA; Dallas). They were 18 to 65 years of age
Inclusion required that the cold had lasted for ≤ 1 calendar day (effectively < 36 hrs). Exclusions not described


InterventionsParticipants took the lozenges every 2 to 3 hours (a total of 6 per day) while awake until cold symptoms resolved
Treatment group: zinc gluconate lozenges containing 5 mg zinc
Placebo group: lozenges contained tannic acid, sucrose octaacetate, quinine


OutcomesDuration and severity of symptoms


NotesLoss to follow-up not described. Analysis was based on intention-to-treat principle. Mean and SD were not reported and were estimated from the figure. The zinc gluconate lozenge contained glycine, which effectively binds to zinc and therefore the free zinc ion level probably was lower than suggested by the total zinc dose


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskUsed drug randomisation code

Allocation concealment (selection bias)Unclear riskThe method of concealment is not described in sufficient detail to allow a definite judgement

Blinding (performance bias and detection bias)
All outcomes
High riskBlinding of participants, key study personnel and outcome assessment ensured, and unlikely that the blinding could have been broken

Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up not described

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasUnclear riskInsufficient information to assess whether an important risk of bias exists

Vakili 2009

MethodsDouble-blind, placebo-controlled trial


ParticipantsSchool-aged Iranian children in the suburb of Mashhad. The age range was 6.5 to 10 years. The participants were free from chronic diseases, such as sickle cell disease or protein-energy malnutrition


InterventionsParticipants took tablet daily for 6 days a week for 5 months
Treatment group: zinc sulfate tablets containing 10 mg zinc
Placebo group: not defined


OutcomesOccurrence and duration of common cold


NotesUsed zinc sulfate tablets. No loss to follow-up


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot described

Allocation concealment (selection bias)Unclear riskThe method of concealment is not described in sufficient detail to allow a definite judgement

Blinding (performance bias and detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of ‘low risk’ or ‘high risk’

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasLow riskThis study was supported by grant of vice president for research, Mashhad University of Medical Sciences

Weismann 1990

MethodsDouble-blind, placebo-controlled randomised trial


Participants6 general practitioners residing in the suburban area of Copenhagen conducted the study. Participants were aged 18 to 65 years. Excluded were pregnant and lactating women, diabetics


InterventionsParticipants took 1 lozenge at 1 to 1.5-hourly intervals
Treatment group: zinc gluconate lozenges (in maltitol syrup) containing 4.5 mg zinc
Placebo group: lozenges contained maltitol syrup with natural flavour


OutcomesOverall assessment of clinical condition assessed by participants using a visual analogue scale


Notes14 participants were excluded because of a lack of records and 1 because of their young age. Mean and SD were not reported and were estimated from the figure. Consecutive allocation method was used in the study


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskNot described

Allocation concealment (selection bias)Unclear riskThe method of concealment is not described in sufficient detail to allow a definite judgement

Blinding (performance bias and detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement of ‘low risk’ or ‘high risk’

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size

Selective reporting (reporting bias)Low riskThe study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified

Other biasUnclear riskThe lozenges were manufactured and supplied by a firm

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Eby 1984The trial was rated of poor methodological quality. A higher incidence of side effects and complaints in the zinc group may have reduced compliance with treatment (no information was provided on whether compliance with treatment was assessed). Intention-to-treat analyses were not conducted; analyses were only conducted on a subset of those originally enrolled in the trial. Inclusion criteria were not adequately addressed and therefore there may have been potential for selection bias to occur. In addition, no information was provided on how allocation to treatment groups was concealed, and the power of the study was not stated.

Eby 2006Used both zinc gluconate nasal spray and zinc orotate lozenges simultaneously

Kartasurya 2012Studied upper respiratory tract infection as a whole, used zinc supplementation for 4 months

McElroy 2003Poor methodological quality. Not a randomised trial

Potter 1993Poor methodological quality. Not a randomised trial

Veverka 2009Poor methodological quality. Measured upper respiratory tract infection as a whole (common cold and seasonal flu)

 
Comparison 1. Zinc versus placebo

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

 1 Duration of cold symptoms141656Mean Difference (IV, Random, 95% CI)-1.03 [-1.72, -0.34]

 2 Subgroup analysis (duration of cold symptoms)145996Mean Difference (IV, Random, 95% CI)-1.07 [-1.43, -0.71]

    2.1 Dose of zinc ≥ 75 mg/day
7620Mean Difference (IV, Random, 95% CI)-1.97 [-3.09, -0.85]

    2.2 Dose of zinc < 75 mg/day
5722Mean Difference (IV, Random, 95% CI)0.13 [-0.54, 0.79]

    2.3 Zinc gluconate lozenges
6798Mean Difference (IV, Random, 95% CI)-0.81 [-1.86, 0.25]

    2.4 Zinc acetate lozenges
6544Mean Difference (IV, Random, 95% CI)-1.21 [-2.69, 0.28]

    2.5 Zinc lozenges
121342Mean Difference (IV, Random, 95% CI)-1.04 [-2.02, -0.05]

    2.6 Zinc syrup
2314Mean Difference (IV, Random, 95% CI)-0.65 [-0.92, -0.39]

    2.7 Children < 16 years age
3561Mean Difference (IV, Random, 95% CI)-0.62 [-0.82, -0.42]

    2.8 Adults
111095Mean Difference (IV, Random, 95% CI)-1.12 [-2.17, -0.06]

 3 Severity of cold symptoms5513Mean Difference (IV, Random, 95% CI)-1.06 [-2.36, 0.23]

 4 Subgroup analysis (severity of cold symptoms)5513Mean Difference (IV, Random, 95% CI)-1.06 [-2.36, 0.23]

    4.1 Zinc lozenges
3199Mean Difference (IV, Random, 95% CI)-1.55 [-3.62, 0.52]

    4.2 Zinc syrup
2314Mean Difference (IV, Random, 95% CI)-0.27 [-1.51, 0.97]

 5 Incidence of common cold21522Risk Ratio (M-H, Random, 95% CI)0.64 [0.47, 0.88]

 
Comparison 2. Zinc versus placebo

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

 1 Number of participants symptomatic after 3 days of treatment3340Odds Ratio (M-H, Random, 95% CI)0.81 [0.27, 2.42]

 2 Number of participants symptomatic after 5 days of treatment3340Odds Ratio (M-H, Random, 95% CI)0.78 [0.32, 1.95]

 3 Number of participants symptomatic after 7 days of treatment5476Odds Ratio (M-H, Random, 95% CI)0.45 [0.20, 1.00]

 4 Time to resolution of cough4453Mean Difference (IV, Random, 95% CI)-1.73 [-3.49, 0.03]

 5 Time to resolution of nasal congestion5605Mean Difference (IV, Random, 95% CI)-0.70 [-1.39, -0.01]

 6 Time to resolution of nasal drainage5599Mean Difference (IV, Random, 95% CI)-1.01 [-2.01, -0.01]

 7 Time to resolution of sore throat4430Mean Difference (IV, Fixed, 95% CI)-0.46 [-0.82, -0.09]

 8 Change in cough symptom score1101Mean Difference (IV, Fixed, 95% CI)-0.23 [-0.26, -0.20]

 9 Change in nasal symptom score2314Mean Difference (IV, Fixed, 95% CI)-0.20 [-1.34, 0.94]

 10 School absence (days)2394Mean Difference (IV, Fixed, 95% CI)-0.66 [-0.99, -0.33]

 11 Antibiotic use2394Odds Ratio (M-H, Fixed, 95% CI)0.27 [0.16, 0.46]

 12 Any adverse event81217Odds Ratio (M-H, Fixed, 95% CI)1.58 [1.19, 2.09]

    12.1 Lozenge formulation
6897Odds Ratio (M-H, Fixed, 95% CI)2.00 [1.40, 2.86]

    12.2 Syrup formulation
2320Odds Ratio (M-H, Fixed, 95% CI)1.03 [0.64, 1.66]

 13 Bad taste121483Odds Ratio (M-H, Fixed, 95% CI)2.31 [1.71, 3.11]

    13.1 Lozenges formulation
101163Odds Ratio (M-H, Fixed, 95% CI)2.66 [1.91, 3.69]

    13.2 Syrup formulation
2320Odds Ratio (M-H, Fixed, 95% CI)1.15 [0.55, 2.39]

 14 Nausea8932Odds Ratio (M-H, Fixed, 95% CI)2.15 [1.44, 3.23]

    14.1 Lozenges formulation
6612Odds Ratio (M-H, Fixed, 95% CI)2.46 [1.56, 3.89]

    14.2 Syrup formulation
2320Odds Ratio (M-H, Fixed, 95% CI)1.24 [0.50, 3.08]

 15 Constipation7874Odds Ratio (M-H, Fixed, 95% CI)1.60 [0.82, 3.10]

    15.1 Lozenges formulation
5554Odds Ratio (M-H, Fixed, 95% CI)2.00 [0.88, 4.55]

    15.2 Syrup formulation
2320Odds Ratio (M-H, Fixed, 95% CI)1.0 [0.31, 3.21]

 16 Diarrhoea6764Odds Ratio (M-H, Fixed, 95% CI)1.89 [0.92, 3.89]

    16.1 Lozenges formulation
4444Odds Ratio (M-H, Fixed, 95% CI)2.09 [0.92, 4.75]

    16.2 Syrup formulation
2320Odds Ratio (M-H, Fixed, 95% CI)1.34 [0.30, 6.09]

 17 Abdominal pain6824Odds Ratio (M-H, Fixed, 95% CI)1.31 [0.83, 2.07]

    17.1 Lozenges formulation
4504Odds Ratio (M-H, Fixed, 95% CI)1.27 [0.76, 2.11]

    17.2 Syrup formulation
2320Odds Ratio (M-H, Fixed, 95% CI)1.52 [0.53, 4.33]

 18 Dry mouth7874Odds Ratio (M-H, Fixed, 95% CI)1.37 [0.95, 1.99]

    18.1 Lozenges formulation
5554Odds Ratio (M-H, Fixed, 95% CI)1.42 [0.95, 2.11]

    18.2 Syrup formulation
2320Odds Ratio (M-H, Fixed, 95% CI)1.13 [0.43, 3.01]

 19 Mouth irritation7822Odds Ratio (M-H, Fixed, 95% CI)1.15 [0.77, 1.73]

    19.1 Lozenges formulation
5502Odds Ratio (M-H, Fixed, 95% CI)1.08 [0.67, 1.73]

    19.2 Syrup formulation
2320Odds Ratio (M-H, Fixed, 95% CI)1.40 [0.62, 3.15]

 
Summary of findings for the main comparison.

Zinc compared with placebo for the common cold

Patient or population: patients with common cold

Settings: outpatient

Intervention: zinc lozenges or syrup

Comparison: usual care

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

Assumed riskCorresponding risk

PlaceboZinc

Duration of cold symptoms (days)The mean duration of cold symptoms ranged across control groups from 5.1 to 9.38 daysThe mean duration of cold symptoms ranged across control groups from 4 to 12.1 days1656
(14 studies1)
++O
low2,3-5

Severity of symptom scoreThe mean severity of symptom score ranged across control groups from 0.4 to 5.61The mean severity of symptom score ranged across control groups from 0.2 to 3.45513
(5 studies6)
++O
low3,5,7,8

Incidence of common cold618 per 1000382 per 1000 (354 to 431)RR 0.64 (0.47 to 0.88)394
(2 studies9)
+OO
very low3,10-12

Number of participants symptomatic after 7 days of treatment563 per 1000373 per 1000 (143 to 508)OR 0.45 (0.2 to 1.0)476
(5 studies13)
++OO
very low14-16

School absence (number of days)The mean days of school absence ranged across control groups from 1.3 to 1.35 daysThe mean days of school absence in the intervention groups was 0.37 lower (0.7 to 0.04 lower)394
(2 studies9)
+OO
very low10,17,18

Antibiotic use330 per 1000127 per 1000 (52 to 200)OR 0.27 (0.16 to 0.46)394
(2 studies9)
++OO
low10,19,20

Any adverse event349 per 1000424 per 1000 (132 to 898)OR 1.58 (1.19 to 2.09)1217
(8 studies)
+++O
moderae21-23

*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% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval
RR: risk 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.

 1No serious study limitations: all the studies had adequately concealed allocation and blinded both participants and study staff to be considered at low risk of bias. Whether free of other bias was unclear in Macknin 1998; Petrus 1998; Turner 2000a; Turner 2000b; Turner 2000c. Petrus 1998 did not adequately describe the sequence generation. Blinding was inadequate in Turner 2000a; Turner 2000b; Turner 2000c.
2Serious inconsistency: there was high statistical heterogeneity. I2 statistic = 89%. The heterogeneity was due to differences in the nature of the different interventions (zinc gluconate versus acetate lozenges, zinc lozenges versus zinc syrup), wide dose ranges, varied duration of symptoms prior to administration of zinc (varying from 24 to 48 hours) and characteristics of the study population (children versus adults).
3No serious indirectness: studies both from low-income and high-income regions have assessed this comparison. Therefore, the result can be confidently generalised to all situations.
4No serious imprecision: though the 95% CI around the pooled effect is narrow, the lower limit does not suggest a clinically important reduction in the duration of cold (a decrease in duration of ≤ 1 day is not shown to be important to patients).
5Publication bias cannot be ruled out.
6No serious study limitation: all the studies had adequately concealed allocation and blinded both participants and study staff to be considered at low risk of bias. Whether free of other bias was unclear and adequate sequence was not generated in one study (Petrus 1998).
7Serious imprecision: the 95% CI around the pooled effect is wide, the lower limit is crossing the point of no effect.
8Serious inconsistency: there was high statistical heterogeneity. I2 statistic = 84%. The heterogeneity may be due to differences in the nature of the different interventions (zinc gluconate or acetate lozenges, zinc sulphate syrup) and dose range (30 to 160 mg/day) as well as mean duration of symptoms prior to administration of zinc (varying from 24 to 48 hours), as well as the characteristics of the study population (children versus adults). However, subgroup analysis was not possible as there were not enough studies for each variable.
9Kurugol 2006b is a community-based intervention including 200 healthy school children and studying the effect of daily administration of 15 mg zinc sulphate syrup over a period of seven months. Vakili 2009 is also a community-based intervention including 200 healthy school children and studying the effect of daily administration of 10 mg zinc sulfate tablets over a period of seven months.
10Serious study limitation: though the study by Kurugol 2006b was of high quality, that by Vakili 2009 was of poor methodological quality.
11Serious inconsistency: there is substantial heterogeneity between the two trials: I2 statistic for heterogeneity = 88%. Both trials showed a benefit with zinc, however the size of this effect was much larger in Vakili 2009. The heterogeneity was due to differences in the trial methodology and the nature of the interventions.
12No serious imprecision: the 95% CI around the pooled effect is narrow. Even the lower limit suggests a clinically important reduction in the incidence rate ratio of cold which is shown to be important to patients.
13No serious study limitations: allocation concealment was unclear in two studies, i.e. Smith 1989 and Weismann 1990, though both the studies blinded both participants and study staff.
14Serious inconsistency: there was high statistical heterogeneity. I2 statistic = 75%. The heterogeneity may be due to differences in the nature of the different interventions (zinc gluconate or acetate lozenges) and dose range (30 to 160 mg/day) as well as mean duration of symptoms prior to administration of zinc (varying from 24 to 48 hours, as well as the characteristics of the study population (children versus adults). However, subgroup analysis was not possible as there were not enough studies for each variable.
15Serious indirectness: only studies from high-income regions have assessed this comparison. Therefore, the result cannot be generalised to all situations.
16No serious imprecision: both limits of the 95% CI suggest a clinically important reduction in proportion of participants given the intervention symptomatic after seven days of treatment.
17Serious inconsistency: there is substantial heterogeneity between the two trials: I2 statistic test for heterogeneity = 64%. Both trials showed reduced days of school absence with intervention, however, the size of this effect was much larger in Kurugol 2006b. The heterogeneity was due to differences in the trial methodology and the nature of the interventions.
18No serious imprecision: though the 95% CI around the pooled effect is narrow, the lower limit does not suggests a clinically important reduction in the duration of school absence (a decrease in duration of ≤ 1 day is not shown to be important to patients).
19No serious inconsistency: there was no statistical heterogeneity. I2 statistic = 0%.
20No serious imprecision: both limits of the 95% CI suggest a clinically important reduction in the rate of antibiotic use with intervention.
21No serious study limitations: all the studies had adequately concealed allocation (except Weismann 1990, in which allocation concealment is unclear) and blinded both participants and study staff to be considered at low risk of bias. Whether free of other bias was unclear in Macknin 1998 and Weismann 1990. Weismann 1990 did not adequately describe the sequence generation.
22No serious inconsistency: there is no statistical heterogeneity. I2 statistic = 21%. Both the lozenges and syrup preparation trials were pooled.
23No serious imprecision: the 95% CI around the pooled effect is narrow. The resulting adverse events from use of zinc are higher and this is significant.