Antihistamin in Common Cold

Antihistamines for the common cold (Review)
De Sutter AIM, Lemiengre M, Campbell H
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2003, Issue 3
http://www.thecochranelibrary.com
Antihistamines for the common cold (Review)

Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Analysis 1.1. Comparison 1 Monotherapy - global evaluation - all trials, Outcome 1 Short term (1-2 days). . . . . 53
Analysis 1.2. Comparison 1 Monotherapy - global evaluation - all trials, Outcome 2 Intermediate term (3-4 days). . 54
Analysis 1.3. Comparison 1 Monotherapy - global evaluation - all trials, Outcome 3 Long term (6-10 days). . . . 55
Analysis 1.4. Comparison 1 Monotherapy - global evaluation - all trials, Outcome 4 Trials with acceptable quality - short
term (1-2 days). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Analysis 1.5. Comparison 1 Monotherapy - global evaluation - all trials, Outcome 5 Trials with acceptable quality -
intermediate term (3-4 days). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Analysis 1.6. Comparison 1 Monotherapy - global evaluation - all trials, Outcome 6 Trials with acceptable quiality - long
term (6-10 days). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Analysis 2.1. Comparison 2 Monotherapy - global evaluation - trials with 1st generation antihistamines, Outcome 1 All
trials - short term (1-2 days). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
trials - intermediate term (3-4 days). . . . . . . . . . . . . . . . . . . . . . . . . . . 58
trials -long term (6-10 days). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Analysis 2.4. Comparison 2 Monotherapy - global evaluation - trials with 1st generation antihistamines, Outcome 4 Trials
with acceptable quality - short term (1 -2 days). . . . . . . . . . . . . . . . . . . . . . . 60
with acceptable quality - intermediate term (3-4 days). . . . . . . . . . . . . . . . . . . . . 60
with acceptable quality - long term (6-10 days). . . . . . . . . . . . . . . . . . . . . . . 61
Analysis 3.1. Comparison 3 Monotherapy - subjective severity assessment of nasal obstruction - all trials, Outcome 1 Mean
severity score after 1 day of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . 62
Analysis 3.2. Comparison 3 Monotherapy - subjective severity assessment of nasal obstruction - all trials, Outcome 2 Mean
severity score after 3-5 days of treatment. . . . . . . . . . . . . . . . . . . . . . . . . 63
Analysis 4.1. Comparison 4 Monotherapy - subjective severity assessment of nasal obstruction - non-sedating antihistamines,
Outcome 1 Mean severity score after 1 day of treament. . . . . . . . . . . . . . . . . . . . 64
Analysis 4.2. Comparison 4 Monotherapy - subjective severity assessment of nasal obstruction - non-sedating antihistamines,
Outcome 2 Mean severity score after 3-5 days of treatment. . . . . . . . . . . . . . . . . . . 64
Analysis 5.1. Comparison 5 Monotherapy - subjective severity assessment of nasal obstruction - 1st generation
antihistamines, Outcome 1 Mean severity score after 1 day of treatment. . . . . . . . . . . . . . 65
Analysis 5.2. Comparison 5 Monotherapy - subjective severity assessment of nasal obstruction - 1st generation
antihistamines, Outcome 2 Mean severity score after 3-5 days of treatment. . . . . . . . . . . . . 66
Analysis 6.1. Comparison 6 Monotherapy - weight of expelled nasal mucus, Outcome 1 3rd day after virus challenge. 67
Analysis 6.2. Comparison 6 Monotherapy - weight of expelled nasal mucus, Outcome 2 4th day after virus challenge. 68
Analysis 6.3. Comparison 6 Monotherapy - weight of expelled nasal mucus, Outcome 3 5th day after virus challenge. 69
Analysis 6.4. Comparison 6 Monotherapy - weight of expelled nasal mucus, Outcome 4 Total weight of nasal mucus over
4-5 days after virus challenge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Antihistamines for the common cold (Review) i
Analysis 7.1. Comparison 7 Monotherapy - subjective severity assessment of rhinorrhoea - all trials, Outcome 1 First
treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Analysis 7.2. Comparison 7 Monotherapy - subjective severity assessment of rhinorrhoea - all trials, Outcome 2 Second
treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Analysis 7.3. Comparison 7 Monotherapy - subjective severity assessment of rhinorrhoea - all trials, Outcome 3 Third
treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Analysis 7.4. Comparison 7 Monotherapy - subjective severity assessment of rhinorrhoea - all trials, Outcome 4 Fourth
treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
Analysis 8.1. Comparison 8 Monotherapy - subjective severity assessment of rhinorrhoea - non sedating antihistamines,
Outcome 1 Fourth treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Analysis 9.1. Comparison 9 Monotherapy - subjective severity assessment of rhinorrhoea - 1st generation antihistamines,
Outcome 1 First treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Outcome 2 Second treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Outcome 3 Third treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Analysis 10.1. Comparison 10 Monotherapy - sneeze counts, Outcome 1 Day 2 after virus challenge. . . . . . . 79
Analysis 11.1. Comparison 11 Monotherapy - subjective severity assesment of sneezing - all trials, Outcome 1 First
treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Analysis 11.2. Comparison 11 Monotherapy - subjective severity assesment of sneezing - all trials, Outcome 2 Second
treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Analysis 11.3. Comparison 11 Monotherapy - subjective severity assesment of sneezing - all trials, Outcome 3 Third
treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Analysis 11.4. Comparison 11 Monotherapy - subjective severity assesment of sneezing - all trials, Outcome 4 Fourth
treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Analysis 12.1. Comparison 12 Monotherapy - subjective severity assessment of sneezing - 1st generation antihistamines,
Outcome 1 First treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Outcome 2 Second treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Outcome 3 Third treatment day. . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Analysis 13.1. Comparison 13 Monotherapy - side effects, Outcome 1 Side effects : all - all trials. . . . . . . . 89
Analysis 13.2. Comparison 13 Monotherapy - side effects, Outcome 2 Side effects : all - non-sedating antihistamines. 90
Analysis 13.3. Comparison 13 Monotherapy - side effects, Outcome 3 Side effects : first generation antihistamines. . 91
Analysis 13.4. Comparison 13 Monotherapy - side effects, Outcome 4 Side effects : sedation - all trials. . . . . . 92
Analysis 13.5. Comparison 13 Monotherapy - side effects, Outcome 5 Side effects : sedation - non-sedating antihistamines. 93
Analysis 13.6. Comparison 13 Monotherapy - side effects, Outcome 6 Side effects : sedation - first generation
antihistamines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Analysis 13.7. Comparison 13 Monotherapy - side effects, Outcome 7 Side effects : gastro-intestinal. . . . . . . 95
Analysis 13.8. Comparison 13 Monotherapy - side effects, Outcome 8 Side effects : sleeplessness. . . . . . . . 96
Analysis 13.9. Comparison 13 Monotherapy - side effects, Outcome 9 Side effect : dry nose. . . . . . . . . . 96
Analysis 13.10. Comparison 13 Monotherapy - side effects, Outcome 10 Side effects : headache. . . . . . . . 97
Analysis 13.11. Comparison 13 Monotherapy - side effects, Outcome 11 Side effects: vertigo, dizziness. . . . . . 98
Analysis 13.12. Comparison 13 Monotherapy - side effects, Outcome 12 Side effects : dry mouth. . . . . . . . 99
Analysis 14.1. Comparison 14 Combination therapy - global evaluation, Outcome 1 Combination therapy - global
evaluation after 2 to 4 days of treatment. . . . . . . . . . . . . . . . . . . . . . . . . 99
Antihistamines for the common cold (Review) ii

Analysis 14.2. Comparison 14 Combination therapy - global evaluation, Outcome 2 Combination therapy - global
evalution at final evaluation time. . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Analysis 15.1. Comparison 15 Combination therapy - side effects, Outcome 1 Side-effects : all. . . . . . . . . 101
Analysis 15.2. Comparison 15 Combination therapy - side effects, Outcome 2 Side-effects : drowsiness, hypersomia and
excessive sleepiness. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Analysis 15.3. Comparison 15 Combination therapy - side effects, Outcome 3 Side-effects : dry mouth. . . . . . 103
Analysis 15.4. Comparison 15 Combination therapy - side effects, Outcome 4 Side-effects : insomnia. . . . . . 103
Analysis 15.5. Comparison 15 Combination therapy - side effects, Outcome 5 Side-effects : gastro-intestinal. . . . 104
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Antihistamines for the common cold (Review) iii

[Intervention Review]
Antihistamines for the common cold
An IM De Sutter1 , Marc Lemiengre1 , Harry Campbell2

1 Department of General Practice and Primary Health Care, Ghent University, Ghent, Belgium. 2 Department of Public Health Sciences,
University of Edinburgh, Edinburgh, UK
Contact address: An IM De Sutter, Department of General Practice and Primary Health Care, Ghent University, 1K3, De Pintelaan
185, Ghent, 9000, Belgium. an.desutter@UGent.be.
Editorial group: Cochrane Acute Respiratory Infections Group.

Publication status and date: Unchanged, published in Issue 3, 2009.
Review content assessed as up-to-date: 27 May 2003.
Citation: De Sutter AIM, Lemiengre M, Campbell H. Antihistamines for the common cold. Cochrane Database of Systematic Reviews
2003, Issue 3. Art. No.: CD001267. DOI: 10.1002/14651858.CD001267.
ABSTRACT
Background
Although antihistamines are prescribed in large quantities for the common cold, there is little evidence as to whether these drugs are
effective.
Objectives
To assess in patients with a common cold the effects of antihistamines in alleviating nasal symptoms, or the shortening the duration of
illness.
Search strategy
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2002, issue 4), which contains
the Acute Respiratory Infections Groups Specilaized Register; MEDLINE (1966 to February 2003); and EMBASE (1987 to December
2002).
Selection criteria
Randomised, placebo-controlled trials on treatment of common cold with antihistamines, used either singly or in combination, in
adults or children.
Data collection and analysis
Two review authors extracted data and trial authors were contacted for further data. Trials were subdivided into monotherapy and
combination therapy. Data on general recovery, nasal obstruction, rhinorrhea, sneezing, and side-effects were extracted and summarized.
Main results
We included 32 papers describing 35 comparisons; 22 trials studied monotherapy, 13 trials a combination of antihistamines with other
medication. A total of 8930 people suffering from the common cold were included. There were large differences in study designs,
participants, interventions, and outcomes. There was no evidence of any clinically significant effect - in children or in adults - on general
recovery of antihistamines in monotherapy. First generation - but not non-sedating - antihistamines have a small effect on rhinorrhea
and sneezing. In trials with first generation antihistamines the incidence of side effects (especially sedation) is significantly higher with
active treatment.
Antihistamines for the common cold (Review) 1
Two trials, studying a combination of antihistamines with decongestives in small children, both failed to show any effect. Of the 11
trials on older children and adults, the majority show an effect on general recovery and on nasal symptom severity.
Authors conclusions
Antihistamines in monotherapy - in children as well as in adults - do not alleviate to a clinical extent nasal congestion, rhinorrhoea and
sneezing, or subjective improvement of the common cold. First generation antihistamines also cause more side-effects than placebo, in
particular they increase sedation in cold sufferers.
Combinations of antihistamines with decongestives are not effective in small children. In older children and adults most trials show a
beneficial effect on general recovery as well as on nasal symptoms. However, it is not clear whether these effects are clinically significant.
PLAIN LANGUAGE SUMMARY
Antihistamines alone are not an effective treatment for the common cold, but might have a small effect in combination with
decongestives
A large number of treatments are used to try and relieve cold symptoms. The common cold is usually caused by a virus and there is
no evidence that antihistamines cause cold symptoms. However, antihistamines are very popular cold treatments, probably because
they are expected to decrease nasal symptoms as they do in allergic reactions (which involve the production of histamines). The review
found no convincing evidence that antihistamines, when used alone, can relieve the common cold. In combination with decongestives,
antihistamines might lead to some general improvement and relief from a blocked and/or runny nose although there is not enough
evidence to be certain.
BACKGROUND by hand to face transfer from fomites. Symptoms arise from an

inflammatory response to the viral antigens (NIAID 2001), chem-
ical mediators are released which affect the vascular tissues of the
Description of the condition nasal epithelium, causing engorgement and an increase of vascular
permeability. This results in sneezing, nasal congestion and rhin-
The common cold is probably the most frequent illness known. orrhea (Nacleiro 1988). Post nasal drip into the throat is the likely
Literally everyone has experienced its typical symptoms of sneez- cause of the irritating cough associated with colds (Curley 1988).
ing, nasal discharge, nasal obstruction, cough, malaise, etc. Chil- The mild fever and aches and pains reflect a generalized response
dren are affected more frequently than adults, with on average six to the viral infection (NIAID 2001).
colds per year compared to the two to four colds per year that the
average adult suffers (NIAID 2001).
The common cold is a mild, self-limiting disease and two-thirds
of sufferers recover within a week. Still, the economic impact is
Description of the intervention
enormous. Foe example, in 1996 in the USA, colds were respon- Since there is no cure or vaccination for the common cold, treat-
sible for 62 million medical contacts, 45 million days of restricted ment is focused on alleviating symptoms. Histamine, which is se-
activity and 22 million days lost from school (NIAID 2001). creted in the nose by mast cells and basophils, is an important
The cause of the common cold is a viral infection. About 30 to mediator of allergic reactions. Nasal challenge with allergens leads
35% of colds are caused by one of more than 100 virus types of to release of histamine, which causes rhinorrhea, nasal congestion
the rhinovirus group . A substantial minority of colds are due to and sneezing. H1 type antihistamines can block these reactions
coronaviruses. Respiratory syncytial virus, influenza and parain- and thus alleviate the symptoms of allergic rhinitis (Nacleiro 1988;
fluenza, and adenovirus have also been implicated. The infection Welliver 1990). Because these symptoms are very similar to cold
is transmitted to the nasal epithelium by airborne droplets, and symptoms, it has been supposed that antihistamines could also be
effective in alleviating common cold symptoms. As a consequence, Types of participants
these drugs - alone or in combination - have been prescribed by Otherwise healthy adults and children, with common cold symp-
physicians and sold over-the-counter in very large quantities. toms that meet the case definition for inclusion in the review.
Nacleiro (Nacleiro 1988) showed however that histamine is not The case definition of the common cold is:
present in increased concentrations in people with experimentally recent onset of symptoms of runny and/or stuffy nose;
induced rhinovirus infection and it thus seems improbable that sneezing, with or without symptoms of headache and
histamine plays a causative role in the origin of common cold cough.
symptoms. Apart from preventing antibody (IgE) dependent re-
lease of histamine from mast cells and basophils, first generation Participants are excluded if they suffer from allergic rhinitis,
antihistamines (but not selective non-sedating antihistamines) also have concurrent lower or chronic respiratory infection or another
inhibit cholinergic responses and cause sedation. Alleviation of chronic disease, atopic eczema, asthma, fever (> 38 C), sinusitis,
common cold symptoms might be due to these effects that do or exudative pharyngitis. They are also excluded if they are taking
however cause most of the side-effects. Efficacy as well as tolerance other medication.
of first generation antihistamines in treating the common cold Source populations are volunteers recruited from the community,
might thus be different from newer non-sedating antihistamines at hospital or community outpatients departments. Additional
(Gaffey 1988). evidence is assessed from studies of healthy volunteers challenged
with rhinovirus in experimental conditions.
Why it is important to do this review Types of interventions

Treatment with antihistamines, either first generation or non-se-
In this review we will summarize evidence on the efficacy of an-
dating, either singly or in combination with other drugs, and ad-
tihistamines (first generation and non-sedating) in relieving cold
ministered either orally or intranasally and compared with a con-
symptoms.
trol group. The control group can be either placebo or no treat-
ment. Dose, frequency of administration, duration of therapy and
frequency of assessment will also be noted.
OBJECTIVES Types of outcome measures

1. Global evaluation of efficacy in the treatment of the
The objectives of this review are to assess, in children and adults
common cold (for example, complete relief, marked, moderate,
suffering from a common cold, the evidence on the efficacy of an-
slight or no relief at all).
tihistamines in alleviating nasal symptoms (nasal congestion, rhi-
2. Decrease in the amount, or duration, of individual
norrhoea, sneezing) and in shortening the duration of the illness.
common cold symptoms - sneezing, nasal congestion,
Also we want to assess the evidence of side effects of antihistamines
rhinorrhoea. These symptoms can be assessed by means of
and hence the risk to benefit considerations of this type of medi-
severity scales (for example, absent, mild, moderate, severe) or by
cation for the common cold.
global evaluation of efficacy (for example, complete relief,
marked, moderate or slight relief, or no relief at all).
3. Objective assessments such as rhinometry to assess mean
nasal airflow, and rhinoscopy to assess redness and swelling of
METHODS
nasal mucosa, nasal secretion and nasal obstruction.
Criteria for considering studies for this review Search methods for identification of studies
Electronic searches
Types of studies
We searched the Cochrane Central Register of Controlled Trials
Randomized controlled clinical trials on the treatment of the com- (CENTRAL) (The Cochrane Library, 2002, Issue 4), which con-
mon cold with antihistamines, used either singly or in combina- tains the Acute Respiratory Infections Groups Specilaized Regis-
tion, in adults and children. ter (06/06/2001 by Ron dSouza); MEDLINE (1966 to February

2003); and EMBASE (1987 to 2002). The EMBASE search strat- to undertake a systematic review consisting of 10 sub-reviews (two
egy was similar to the MEDLINE search strategy. interventions with five outcomes).
MEDLINE Pooling of data was restricted due to the limitations of the data
[exp common-cold/dt, th or exp respiratory-tract-infections/dt,th extracted. In the meta-analyses, four types of data were entered,
or exp cough/dt,th or exp nasal-obstruction/dt,th or exp sneezing/ namely the proportion of participants with improvement at a cer-
de or exp rhinovirus-infection/de] and [exp histamine-H1-antag- tain time point, incidence of side-effects, objectively measured
onists/all subheadings or exp anti-allergic-agents/all or exp his- outcomes (for example, weight of nasal secretion) and subjective
tamine-antagonists, non-sedating/all or exp antazoline/all or exp severity ratings for nasal obstruction, rhinorrhoea and sneezing.
methapyrilene/all or exp pyrilamine/all or exp tripelennamine/all These subjective ratings were mostly presented in the papers as or-
or exp clemastine/all or exp dimenhydrinaat/all or exp diphenhy- dinal rating scores. The scales used were different between studies:
dramine/all or exp doxylamine/all or exp brompheniramine/all or four-point (absent, mild, moderate, severe), or five-point (absent,
exp chlorpheniramine/all or exp dimethindene/all or exp pheni- mild, moderate, severe and very severe). Since word codes were the
ramine/all or exp triprolidine/all or exp promethazine/all or exp same for the different severity steps in both scales it is likely that
cetirizine/all or exp meclizine/all or exp hydroxyzine/all or exp participants interpreted the four lower steps alike, but that in the
astemizone/all or exp cyproheptadine/all or exp loratadine/all or five point scale the highest step is subdivided in two (severe and
exp terfenadine/all]. very severe). Average scores are all lower than three, suggesting that
few participants gave high ratings. Also, the average ratings are not
systematically higher in the five-point trials. Therefore we judged
Searching other resources ratings from these different scales as comparable and entered data
We found further references by following-up references in iden- from both scales, unaltered, in the meta-analyses.
tified papers and review articles; appealing at presentations and Conclusions on effectiveness are primarily based on the subjective
workshop sessions for further articles at a major international con- severity assessments. We considered an overall effect as clinically
ference on Acute Respiratory Infections in Canberra 1997; by cor- significant when antihistamines increased the number of partici-
respondence with recognized experts in the field requesting details pants reporting overall improvement by at least 15% in compari-
of further published and unpublished data; by contacting phar- son with placebo treatment. With regard to the individual symp-
maceutical companies producing antihistamines for published or toms we considered an average reduction by one point (for exam-
unpublished data on their products. ple, moderate to mild) on the subjective severity scales as clinically
The only restriction was that we limited the search to papers that significant.
were published after 1950.
Assessment of risk of bias in included studies

Data collection and analysis Two review authors (ADS, ML) assessed the quality of the articles
that met the criteria. Criteria used were:
1. the scoring system described by Smith (Smith 1993); this
Selection of studies assigns points for 11 criteria including clarity of research goal,
subject definition, equivalence of groups, blinding of investigator
Two of the four review authors screened the titles and abstracts of
and participants, dropouts and clinical significance;
citations. Trials failing to meet the inclusion criteria were excluded
2. the scoring system described by Jadad (Jadad 1996), which
from the review. Articles identified which did not have an abstract
assesses randomisation, blinding and drop-outs. This second
or had a limited abstract were assessed by one review author for
score was added to the first to allow separate evaluation of these
inclusion.
three essential quality items. Disagreements on scoring between
reviewers were resolved by discussion and consensus.
Data extraction and management
Two review authors (ADS, ML) performed data extraction. We
contacted trial authors for additional data if necessary. Trials on
small children and trials on older children and adults were anal- RESULTS
ysed separately. All trials are subdivided into two major groups
(monotherapy and combination therapy). For each of these in-
tervention groups, data on five different outcomes (general recov-
ery, nasal obstruction, rhinorrhoea, sneezing, side effects) were ex-
Description of studies
tracted. The trials showed important differences in study partici- See: Characteristics of included studies; Characteristics of excluded
pants, interventions, outcomes and designs. Therefore, we chose studies.

Results of the search imentally infected with cold viruses (n = 702) and in 24 trials
participants had community acquired colds. All experimentally
We identified 46 papers. Of these, 32 met the final criteria for
infected patients and patients from three trials with community
inclusion. There was complete agreement between the investiga-
acquired colds were kept under observation during the first days of
tors assessing the papers. Fourteen papers describing 19 differ-
treatment. It was often not clear how participants were recruited.
ent comparisons were excluded: in six comparisons there was no
The majority were volunteers recruited among university students,
placebo or no treatment group; four studied whether antihis-
in companies or by advertisements within the community. Only
tamines could prevent common colds; three included participants
in one adult trial and in the pediatric trials was it explicitly stated
with other diagnoses than common cold, three included explicitly
that participants seeking medical help for their cold symptoms
allergic rhinitis together with common cold patients; in one study
were enrolled.
the intervention treatment was not an antihistamine; and in one
In most participants, the duration of symptoms before inclusion
study outcome criteria were unclear.
was less than 48 hours. In four trials this was up to three days,
In the Characteristics of included studies table details on qual-
in one up to seven days. In one pediatric trial, the mean duration
ity scores, included population, setting, inclusion and exclusion
of symptoms was six to seven days, but there was a very wide
criteria, interventions and dosage, outcome measures and main
range (1to 365 days). In one experimental trial, participants started
methodological shortcomings, are summarized per study.
therapy before virus inoculation.
In total 35 randomized controlled trials (RCTs) were described in
Duration of therapy varied between one dose and seven days.
the 32 selected papers. One trial used a crossover design. The inter-
The studies were performed in the USA (16), UK (5), Sweden (2),
ventions consisted of a combination of antihistamines with other
Peru (2), Switzerland (2), Mexico (1), Finland (1), Belgium (1),
medications (13 comparisons), or antihistamines in monother-
Thailand (1). In one, the country of origin was not clear.
apy. Eight trials compared non-sedating antihistamines (lorata-
Only one study reports independent financing. All others were
dine, terfenadine, cetirizine,astemizole) with placebo, 27 compar-
fully or partly supported by pharmaceutical companies that pro-
isons were made with first generation antihistamines (promet-
vided grants, supplied the drugs in question or gave assistance with
hazine, clemastine, triprolidine,pheniramine, chlorpheniramine,
the studies. In nine studies, the source of financing is not men-
brompheniramine, dexbrompheniramine, phenidramine, tripe-
tioned.
lennamine, doxylamine, diphenhydramine, azalatadine, thonzy-
lamine, benadryl).
The 32 papers involved 8930 patients suffering from the common
cold. Most studies included adult participants. In four trials, young Risk of bias in included studies
children were studied: three studies were on children less than five The quality of the studies varied between 5 and 13 using the Smith
years old, and one on children between the age of two and 15. In and Feldman scoring list (maximum 13), and between two and five
four other trials the minimal age for inclusion was six (three trials) on the Jadad score (maximum five). The majority of the studies
or 12 (one trial). was of good quality: in 29 of the 32 papers trials scored nine or
Inclusion criteria were quite diverse. In the vast majority of studies more on the Smith and Feldman score, and 28 of the 32 scored
the clinical symptoms of common cold, required for inclusion, three or more on the Jadad scale; in one trial, data are insufficient
were described in detail. Mostly a minimal score on a symptom to judge quality. Follow up varies between 67% and 100%. In 25
severity scale was used based on the symptoms described by Jack- trials follow-up is more than 90%. In two trials data on this issue
son (Jackson 1958) (headache, sneezing, chilliness, sore throat, are unclear.
nasal discharge, nasal obstruction, cough and malaise); in three
trials only one symptom was required (nasal blocking due to acute
rhinitis, rhinorrhoea). In six studies the participants own judge-
ment of having a cold was sufficient. In one study the physician Effects of interventions
established the diagnosis of Upper Respiratory Tract Infection. In
the trials with experimentally infected volunteers it is not always
clear whether infected participants were also symptomatic. Part 1: Antihistamines in monotherapy for older
A history of allergic rhinitis was an exclusion criterion in 25 papers, children and adults
a present attack of allergic rhinitis in two, in one trial allergic
participants were removed afterwards and in four trials allergic
rhinitis is not mentioned. Section 1: Global evaluation of efficacy
Trials took place in very different settings: at universities, in lab-
oratory settings, allergic clinics, pediatric departments, family
medicine departments, Ear Nose and Throat departments. Seven
(1) Systematic review
trials were multi-center. In eight trials, participants were exper-

Twelve trials, evaluating 5778 participants, assessed the global effi- as beneficial in almost as many participants with placebo as with
cacy of antihistamines on the course of the common cold in older active treatment (p = 0.77).
children and adults. Fourthly, in the study of Howard (Howard 1979), 271 participants
Four trials using first generation antihistamines showed some ef- daily gave their global evaluation of the received treatment for
fect. seven days of therapy (chlorpheniramine or placebo); this was
Firstly, a Medical Research Council trial MRC (MRC (Part II) on a five point scale (markedly improved, moderately improved,
1950) included 1550 participants in order to study the effective- slightly improved, no improvement, worse). There is no significant
ness of thonzylamine. More participants were improved or cured difference from the placebo group in the number of participants
after one day with thonzylamine than with placebo (p = 0.04), but feeling markedly to moderately improved after one day or six days
this was not the case after two or seven days. However, 25 % of of treatment (day 1: p = 0.11; day 6: p = 0.55).
participants were lost to follow-up. Fifthly, in the trial of Henauer (Henauer 1988) the effectiveness
Secondly, in the trial of Bye (Bye 1980) the effect of tripilodine of terfenadine was studied. In this trial, recruitment was difficult:
in 180 cold episodes was studied. Some participants were entered at first a number of participants not answering to eligibility cri-
several times while having several cold episodes during the course teria were entered and these were later removed. We report the
of the study. In significantly more cold episodes, participants at results of the eligible group: therapy was evaluated as moderately
final evaluation (8 to 10 days after the start of therapy) were im- to excellently efficacious by more patients in the terfenadine group
proved by tripilodine compared with placebo (p = 0.009). than in the placebo group, but this difference was not statistically
Thirdly, Crutcher (Crutcher 1981), examining the effect of chlor- significant (p = 0.10).
pheniramine in 106 adults, found that volunteers considered Sixthly, Gaffey (Gaffey 1988) also studied the effect of terfenadine
themselves significantly better in comparison to the start of the and included 250 participants. The proportion of participants
cold, after two to seven days with active treatment when compared with complete or marked symptom relief at study conclusion (3.5
with placebo (p = 0.05). days) was not significantly different between the treatment groups
Finally, Gwaltney (Gwaltney 1997), studying the effect of (p = 0.55).
brompheniramine in 225 experimentally infected symptomatic Seventhly, in the study of Berkowitz (Berkowitz 1991) - which
adult volunteers, asked participants at final evaluation to rate their again studied the effect of terfenadine - the global evaluation
global improvement on a 10 point visual analogue scale (VAS). Par- by physicians on a five point scale (complete relief, marked re-
ticipants in the active treatment group scored significantly higher lief, moderate relief, slight relief, no relief or worse) after four to
(p < 0.01). five days of treatment was similar in both treatment and placebo
Eight other trials - four studying non-sedating antihistamines - groups. Finally, Gwaltney (Gwaltney 1996) found no difference
failed to show any significant beneficial effect. in overall treatment effect between clemastine and placebo in 150
Firstly, Cowan (Cowan 1950) studied phenidramine and tripelen- experimentally infected participants. In both the aforementioned
namine in 767 colds occurring in 367 students. The students who studies more detailed data on this outcome are not reported.
volunteered to participate were especially susceptible to colds that
could mean that they differed in some way from the average cold
patients. Treatment allocation was alternate presentation and it is (2) Meta-analysis
not clear whether the investigators were blinded. The proportion
of colds lasting less than two days (p = 0.14), or taking less than
4 days (p = 0.60), was compared between treatment groups: there
was no significant difference. (a) Results of pooled data
Secondly, Lorriman (Lorriman 1950), enrolled 1744 adults in or-
Data from eight of the trials was entered into a meta-analysis
der to study the effect of antistin. Inclusion and exclusion criteria
(Cowan 1950; Lorriman 1950; MRC (Part II) 1950; Tebrock
were not clear, treatment was alternately allocated and a substan-
1973; Howard 1979; Bye 1980; Henauer 1988; Gaffey 1988).
tial number of participants were lost to follow-up. The proportion
All these trials used as their outcome the proportion of participants
of participants cured after one or seven days was not significantly
with beneficial effect in both treatment groups at a certain time
different (1 day: p = 0.17; day 7: p 0.73).
point after the start of the treatment. Yet, different populations
Thirdly, in the study by Tebrock (Tebrock 1973), 556 participants
and different interventions are studied, and results must be con-
with common cold and cough were included with the intention
sidered with care. Seven trials show the opinion of the participants,
of studying the effect of benadryl. In the available report it is
in one trial (Tebrock 1973) only the physicians evaluation is avail-
not clear whether or not investigators were blinded. There is no
able. Some have methodological shortcomings as mentioned in
mention of the exclusion of participants with allergic rhinitis and
the systematic review. Two trials (Cowan 1950; Lorriman 1950)
the duration of symptoms before inclusion is unknown. After three
are of definite low quality and overall results are presented with
days of treatment, the response was judged by the investigators
and without these two trials.

Following data are pooled (see Comparisons and Data, compar- got a cold. Nasal patency was measured hourly by active anterior
ison nr. 1 and 2): rhinometry, before and after two treatment administrations on the
(i) Comparison of proportion of patients with beneficial third treatment day. Nasal flow rates were not different between
effect: all trials participants on intranasal diphenhydramine or placebo (p-values
short term effect (one to two days) not mentioned).
intermediate term effect (three to four days) Thirdly, Doyle (Doyle 1988) inoculated 40 adult volunteers with
long term effect (six to ten days) cold viruses and twenty-seven developed a cold. Rhinomanometry
was performed daily. In these 27 participants chlorpheniramine
(ii) Comparison of proportion of patients with beneficial
had no effect on nasal airway patency measured as average inspi-
effect: trials with first generation antihistamines
ratory work/litre (p-values not mentioned).
short term effect (one to two days)
Finally, Henaue(r Henauer 1988) measured mean nasal airflow
intermediate term effect (three to four days)
two hours and 24 hours after one administration of terfenadine or
long term effect (six to ten days)
placebo. Only sixteen participants (eight with terfenadine, eight
In both comparisons there is a short-term beneficial effect of an- with placebo) from a total of 63 eligible participants were examined
tihistamines on general recovery when the methodologically infe- and it is not clear how they were selected out of the total group.
rior studies are left out (p < 0.01). The difference is however small, Nasal airway patency was increased in the terfenadine group com-
with a number needed to treat (NNT) of about 14. None of the pared to the placebo group, but the difference between treatment
other comparisons showed any significant effect. groups was only significant after two hours (p = 0.0045).
Pooling of these results in a meta-analysis was not possible: dif-
ferent measurement methods were used and/or results are only
graphically displayed in the papers. A short term beneficial effect
(b) Data not included in the meta-analysis
of terfenadine (a non-sedating antihistamine) is found only in one
See Table 1. trial (Henauer 1988). This has methodological shortcomings as it
Some data could not be entered into the meta-analysis because considers a subgroup of sixteen patients and the selection process
other outcome measures were used, or adequate data were not is unclear. Therefore, we conclude that first generation antihis-
available in the papers. This comprises data from five trials and tamines do not change nasal patency. Whether or not there is a
792 participants. Two show some effect: in the trial by Crutcher short-term effect of terfenadine should be investigated further.
(Crutcher 1981), insufficient data were reported to judge the size
of this effect; in the trial by Gwaltney (Gwaltney 1997), partici-
pants in the active treatment group rated their global improvement (2) Effect on subjective severity of nasal obstruction on
after four days of treatment on a 10 point VAS 1.1 better than different treatment days.
in the placebo group which can hardly be of clinical significance. Seven trials used this outcome measure.
Therefore it is unlikely that results of these trials would change
the conclusions of the meta-analysis.
(a) Systematic review

Section 2: Effect on nasal patency Five trials show no favourable treatment effect.
Firstly, in the study by Bye (Bye 1980) severity ratings of nasal
obstruction using a four-point scale noted in a diary did not de-
(1) Effect on objectively measured nasal patency crease significantly more in the 59 participants receiving triproli-
See Table 2 dine compared with the 60 participants taking placebo.
Four trials measured changes in nasal patency in an objective way. Secondly, in the study by Gaffey (Gaffey 1988) 250 participants
Firstly, Aschan (Aschan 1974b) performed repeated rhinometric registered their mean severity score twice a day, three hours after
recordings, at 30 to 50 min intervals, in 30 participants with nasal each dose of terfenadine (in total seven doses). A four-point scale
blocking due to acute rhinitis after one administration of clemas- was used. At one time point, after the sixth dosage on day three,
tine or placebo. Increase of nasal patency is considered as positive a significant difference was found: nasal stuffiness was worse with
rhinomanometric change. In the active treatment group, changes terfenadine (p < 0.05).
were positive in two participants out of 15 participants, compared Secondly, in the trial by Berkowitz (Berkowitz 1991) - including
with none in the placebo group (p 0.46). 100 participants - physicians used a four point scale to evaluate the
Secondly, Gaffey (Gaffey 1987a) studied the effect of diphenhy- severity of nasal obstruction after four or five days of treatment,
dramine intranasally in 23 experimentally infected participants. approximately three hours after the last dosage of trial medication
Trial medication was started 24 h after virus inoculation and before (terfenadine or placebo), and found similar severity in both treat-
any symptoms developed. Only 17 of these participants actually ment groups (p = 0.084).

Thirdly, Gwaltney (Gwaltney 1996) - in 150 experimentally in- mean severity assessment of nasal obstruction after three to
oculated and symptomatic patients - recorded the subjects assess- five days of treatment
ments of severity on a five point scale and found no significant
(Gaffey 1988, Gwaltney 1996; Gwaltney 1997; Muether 2001:
difference in favour of clemastine (p > 0.10).
day three, Berkowitz 1991: day four to five)
Finally, Muether (Muether 2001) studied the effect of loratadine
(Comparison 5) Subjective severity assessment of nasal obstruction
in 66 participants. This study design was different: treatment was
- non-sedating antihistamines
started seven days before virus inoculation and continued five days
mean severity assessment of nasal obstruction after one day
afterwards. Severity scores (five point scale) of nasal obstruction
of treatment
were recorded during five days after inoculation for participants
mean severity assessment of nasal obstruction after three to
with proven infection (but not necessarily symptoms) (n = 53).
five days of treatment
Only 37 of these participants got a clinical cold. There was no
significant difference in severity scores between placebo and lo- (Gaffey 1988, Gwaltney 1996; Gwaltney 1997; Muether 2001:
ratadine (p > 0.10). day three, Berkowitz 1991: day four to five)
In contrast with these results, two trials do show some effect. None of these comparisons shows any significant effect in favour
Firstly, Gwaltney (Gwaltney 1997), using a similar experimental of antihistamines.
design (n = 225) as in the 1996 study, found a significant effect However, when looking at the pooled results after three to five days
from brompheniramine on subjective nasal obstruction on the of therapy with non-sedating antihistamines, we see a significantly
third day of therapy (p = 0.04) but not on the other days. higher severity score in the participants receiving antihistamines
Secondly, Ectors (Ectors 1994), studying the effect of cetirizine in (p = 0.02).
40 experimentally infected participants, found a significant larger (ii) Data not entered in the meta-analysis (see Table 3)
decrease in nasal obstruction severity score after two days of treat-
Results of the trial Ectors (Ectors 1994) on 40 experimentally
ment in the active treatment group (p = 0.035). It is not clear from
infected symptomatic participants, and of the trial by Bye (1980)
the available report how these scores were obtained.
on 119 naturally acquired colds could not be entered in the meta-
analysis (due to inadequate data in the report). Ectors 1994 reports
a significant effect of cetirizine after two days of treatment. Bye
(b) Meta-analysis 1980 reports no effect from triprolidine. It is very unlikely that
(i) Results of pooled data. adding the results of these studies would change the conclusion of
Data from five trials were entered into a meta-analysis (Gaffey the meta-analysis.
1988; Berkowitz 1991; Gwaltney 1996; Gwaltney 1997; Muether
2001). These trials are however quite different from one another: (3) Effect on other outcomes
two trials are on participants with natural colds, three on exper-
See Table 3
imentally infected participants; three studied non-sedating anti-
In the study by Doyle (Doyle 1988), 27 participants who devel-
histamines; two first generation antihistamines; three used a five
oped a cold after experimental virus inoculation were interviewed
point severity score, two a four point severity score. The trial of
on days three to six after inoculation. The severity scores (mild,
Muether had a special design and only 70% of participants had a
moderate, severe) obtained on these four days by interview were
clinical cold. In Gaffeys trial we only have data on the single time
summed and averages are compared between chlorpheniramine (n
point, when a significant difference was found.
= 12) and placebo (n = 15) treated treatment groups: there was
The following comparisons were made (see Comparisons and
no significant difference (p = 0.11). In the same study the average
Data, comparison nr. 3 to 5):
number of days with nasal obstruction was counted in both treat-
(Comparison 3) Subjective severity assessment of nasal obstruction
ment groups. There was no significant difference (p = 0.14).
- all trials
In the trial by Tebrock (Tebrock 1973), 75 % or 341 of the in-
mean severity assessment of nasal obstruction after one day
cluded patients suffered from nasal congestion. The proportion of
of treatment
these patients with improvement of nasal congestion after one and
mean severity assessment of nasal obstruction after three to
two days of treatment, and the proportion in which this symptom
five days of treatment
had disappeared after three days, is recorded. There is a trend in
(Gaffey 1988; Gwaltney 1996; Gwaltney 1997; Muether 2001: favour of benylin on the second day (p = 0.06).
day 3; Berkowitz 1991: day four to five) In one trial rhinoscopia was performed. In the trial by Henauer
(Comparison 4) Subjective severity assessment of nasal obstruction (Henauer 1988) the same participants who underwent rhinometry
- first generation antihistamines (see Objectively measured nasal patency) were also examined by
mean severity assessment of nasal obstruction after one day rhinoscopia. At two and 24 hours after the first tablet of terfenadine
of treatment or placebo, redness, swelling, obstruction and secretion were less

severe in participants on terfenadine when compared with placebo (b) Meta-analysis
(no p-values mentioned). In this trial there were however several (i) Results of pooled data (see Comparisons and data: comparison
methodological problems. nr.6)
Data on expelled mucus weight at days three, four and five after
virus challenge and the total weights over the observation periods
were pooled.
Section 3: Effect on rhinorrhoea
On the third and fourth day after virus challenge (participants
had symptoms for at most 24 to 48 hours), nasal secretions were
significantly less with active treatment. On the third day of treat-
ment, the volunteers produced, on average, 1.1 gram mucus less
(1) Effect on weight of expelled nasal mucus (p=0.02) and on the fourth day 0.30 gram less (p = 0.007). This
effect is due to first generation antihistamines. The one trial with
a non-sedating antihistamine (Muether 2001: loratadine) clearly
shows no effect on nasal secretion weight.
In four trials (Doyle 1988; Gaffey 1987a; Gaffey 1987b; Muether
(a) Systematic review. 2001), all with a limited number of participants, the total weight
Seven trials - all on experimentally infected participants - weighted of secretions over several treatment days was measured. There was
the amount of mucus expelled by the test persons. no significant decrease in total weight of secretions with antihis-
Gaffey performed two trials: firstly (Gaffey 1987a), the effect of tamines (p = 1). So, in an experimental setting, first generation
intranasally administered diphenhydramine was compared with antihistamines can decrease nasal mucus production three to four
placebo in 23 infected volunteers, and secondly (Gaffey 1987b), days after virus inoculation, although total excretion seems to be
the effect of orally administered chlorpheniramine was compared unchanged.
with placebo in 28 infected volunteers. Not all of these participants (ii). Data not entered in the meta-analysis.
developed a clinical cold. Expelled mucus was weighted from one One trial, Ectors (Ectors 1994) could not be entered because stan-
to five days after virus challenge in the first trial, and in the second dard deviations were not reported. The results of this trial confirm
trial from day three to six. No significant differences were found the results of the meta-analysis.
(p-values all > 0.2).
Doyle (Doyle 1988) measured average weight of expelled mucus (2) Effect on the subjective severity assessment of
from the second until the sixth day after virus challenge in 27 rhinorrhoea on different treatment days.
symptomatic test persons. There was no significant difference be- Ten trials used this outcome measure.
tween treatment groups (chlorpheniramine vs placebo) on any of
these days (p-values > 0.2).
Ectors (Ectors 1994) studied expelled mucus weight in 40 experi-
mentally inoculated volunteers. Treatment was started when par- (a). Systematic review
ticipants developed cold symptoms. Nasal mucus weight decreased Five trials (Bye 1980; Gaffey 1988; Berkowitz 1991; Muether
from 4.62 g to 2.9 g in the cetirizine group, versus 3.59 g to 2.60 2001;Ectors 1994) failed to show any effect of antihistamines. In
g in the placebo group. The differences were significant on both these trials severity of rhinorrhea was assessed in the same way as
observations days after start of treatment (day two (p = 0.001) and severity of nasal obstruction (see effect on subjective severity of
day three (p = 0.03). Gwaltney (Gwaltney 1996) studied 150 vol- nasal obstruction on different treatment days.
unteers with cold symptoms after experimental virus inoculation. These trials studied respectively: triprolidine (first generation), ter-
Mucus weight was measured daily for five days after inoculation fenadine, loratadine and cetirizine (non-sedating).
but no significant effect was found using clemastine. Gwaltney In five trials some effect was found.
(Gwaltney 1997) examined the effect of chlorpheniramine in 225 Firstly, in the study by Howard (Howard 1979), participants were
experimentally infected symptomatic volunteers: on the third and kept under observation during the first two days of treatment.
fourth day after virus challenge significantly less mucus was ex- Severity scores were measured on a four point scale every two
pelled in the active treatment group (p-values < 0.01). hours (daytime) during 48h, and afterwards three times a day. The
The special design of the trial of Muether (Muether 2001) is al- total study observation period was seven days. On 18 of the 24
ready described (see Effect on subjective severity of nasal obstruc- time points rhinorrhoea severity score was significantly lower with
tion). Secretions were weighted from the second to the sixth day chlorpheniramine (p-values not mentioned).
after virus challenge. No significant differences were found be- Secondly, in the study by Turner (Turner 1997), 1000 participants
tween the treatment groups (loratadine versus placebo, p-values > were kept under observation during a whole winter and were en-
0.2). tered into the trial when developing a cold. Four hundred and

three participants developed a cold and the effect of clemastine mean severity assessment of rhinorrhoea - second day of
was compared with placebo. Rhinorrhoea severity was scored from treatment
day two until four of treatment on a five-point scale and was sig- mean severity assessment of rhinorrhoea - third day of
nificantly less severe on day three and four with active treatment treatment
(p < 0.001). mean severity assessment of rhinorrhoea - fourth day of
Thirdly, Eccles (Eccles 1995) studied the effect of doxylamine treatment
in 688 cold patients. Severity scores were recorded twice daily
These comparisons show that there is some effect of antihistamines
during three days, on a five-point scale. Rhinorrhoea severity scores
on days two, three and four (p < 0.001) which means that the
were significantly lower in the doxylamine group on the second
objectively measured decrease in nasal secretion is also subjectively
treatment day (p < 0.01).
noticeable. The overall effect of all antihistamines is due to the
Finally, the studies by Gwaltney (Gwaltney 1996; Gwaltney 1997),
first generation antihistamines. Trials with non-sedating antihis-
respectively studied clemastine in 150 experimentally infected
tamines show no effect on rhinorrhoea, while pooling results of
symptomatic volunteers, and brompheniramine in 225 experi-
studies with only first generation antihistamines shows a more
mentally infected symptomatic volunteers, also scoring rhinorrhea
significant effect. This effect seems to increase with duration of
severity on a five point scale. Significantly lower scores were found
treatment.
with active treatment on treatment days two and three in the 1996
Still the differences are very small. A difference of one would mean
trial (p < 0.05), and on treatment days 2 to 4 in the 1997 trial
that participants rate, on average, one severity category lower with
(day two p < 0.05, day three and four: p < 0.02).
active treatment than with placebo (e.g. from moderate to mild).
The observed mean difference is however at most 0.24, which is
not clinically significant.
(b) Meta-analysis
(i) Results of pooled data.
Data of seven trials can be pooled (Gaffey 1988;Berkowitz (c) Data not entered in the meta-analysis
1991; Eccles 1995;Gwaltney 1996; Gwaltney 1997; Turner 1997;
Muether 2001). See Table 4
Again we point out that in spite of the fact that data were obtained Data from three trials could not be entered in the meta-analysis.
in similar ways, these trials are still quite different from one an- In the study of Howard (Howard 1979) chlorfeniramine (first
other in the way that participants were recruited or infected, in generation) has some significant effect and in the study of Ectots
treatment, or in the way severity was assessed. (Ectors 1994) cetirizine (non-sedating) has not. This is in line with
The following comparisons were made (see Comparisons and the results of the meta-analysis. The study of Bye (Bye 1980) is the
data, comparisons nr.7-9): only trial in which a first generation antihistamine (triprolidine)
Comparison7. Subjective severity assessment of rhinorrhoea -all had no effect on rhinorrhoea on any of the observation days. It
trials is however unlikely that adding data of this study would alter the
mean severity assessment of rhinorrhoea - first day of conclusion of the meta-analysis.
treatment
mean severity assessment of rhinorrhoea - second day of
(3) Effect on other outcomes
treatment
mean severity assessment of rhinorrhoea - third day of In the study by Doyle (Doyle 1988) of 27 participants who de-
treatment veloped a cold after experimental virus inoculation, the severity
mean severity assessment of rhinorrhoea - fourth day of scores of rhinorrhoea (mild, moderate, severe) obtained by inter-
treatment view on four treatment days were summed and the averages are
compared between the chlorpheniramine (n = 12) and placebo
Comparison 8. Subjective severity assessment of rhinorrhoea non- (n = 15) treated participants: there was no significant difference
sedating antihistamines (p = 0.16). Doyle also counted the average number of days with
mean severity assessment of rhinorrhoea - fourth day of rhinorrhea in both treatment and placebo groups. There was no
treatment significant difference (p = 0.6).
Rhinoscopia was performed with assessment of nasal secretion
(this day was chosen because the most complete data was available)
in the trial by Henauer (Henauer 1988) : at two hours and 24
Comparison 9. Subjective severity assessment of nasal
h after the first tablet of terfenadine or placebo, secretion were
rhinorrhoea - first generation antihistamines
less severe in participants with terfenadine when compared with
mean severity assessment of rhinorrhoea - first day of placebo (Table 5). Methodological problems with this trial are
treatment mentioned previously (see Effect on nasal obstruction).

Section 4: Effect on sneezing In the study of Howard (Howard 1979) at all time points sneezing
severity scores were significantly lower with chlorpheniramine (p-
values not mentioned).
(1) Effect on sneeze count In the study of Bye (Bye 1980), on day two, there was a significantly
larger reduction in mean severity score of patients treated with
tripilodine (p-values not mentioned).
In the study of Turner (Turner 1997), sneezing severity was signifi-
(a) Systematic review cantly less severe on days two, three and four with active treatment
(p < 0.001).
In two trials (Gwaltney 1996; Gwaltney 1997) - both on exper-
Eccles (Eccles 1995) found that sneezing severity scores were sig-
imentally infected volunteers - the number of sneezes during the
nificantly lower in the doxylamine group on day two and three (p
observation period was counted. In 1996, the effect of clemastine
< 0.01).
in 150 volunteers with cold symptoms after inoculation was stud-
Finally, the studies of Gwaltney (Gwaltney 1996; Gwaltney 1997),
ied. Sneezes were counted from day two until day five after in-
respectively studied clemastine in 150 experimentally infected
oculation. There were significantly fewer sneezes with clemastine
symptomatic volunteers. Significantly lower scores were found
on days three and five (p < 0.001). In the study of 1997 on 225
with active treatment on treatment days two and three in the 1996
volunteers, sneezes were counted from day one to day four after
trial (day 2: p < 0.02, day three: p < 0.01), and on treatment days
inoculation, there was a significant difference on all observation
two and four in the 1997 trial (p < 0.001).
days in favour of brompheniramine (day two and three : p < 0.001,
day 4 : p < 0.02).
(b) Meta-analysis
(i) Results of pooled data
(b) Meta-analysis (see Comparisons and data - comparison
Data from six trials can be pooled (Berkowitz 1991; Eccles 1995;
nr. 10)
Gwaltney 1996; Gwaltney 1997; Turner 1997; Muether 2001). As
Data on sneeze counts on days two, three and four were pooled. mentioned before, these trials are quite different from one another.
Overall there were significantly fewer sneezes on each of these days The following comparisons are made (see Comparisons and Data
(p < 0.001). The effect was most pronounced on day three when , comparison nr.11-12):
volunteers in the active treatment group sneezed almost three times Comparison 11. Subjective severity assessment of sneezing -all
less than in the placebo group. Both trials used first generation trials
antihistamine (clemastine and brompheniramine). mean severity assessment of sneezing - first day of treatment
mean severity assessment of sneezing- second day of
treatment
(2) Effect on subjective severity assessments of sneezing on mean severity assessment of sneezing- third day of treatment
different treatment days
mean severity assessment of sneezing - fourth day of
Ten trials used this outcome measure treatment
Comparison 12. Subjective severity assessment of sneezing - first
generation antihistamines
(a) Systematic review mean severity assessment of sneezing - first day of treatment
mean severity assessment of sneezing - second day of
Four trials (Gaffey 1988; Berkowitz 1991; Muether 2001;Ectors
treatment
1994) failed to show any effect. . In these trials severity of sneezing
mean severity assessment of sneezing - third day of
was assessed in the same way as severity of nasal obstruction. For the
treatment
description: see effect on subjective severity of nasal obstruction
mean severity assessment of sneezing - fourth day of
on different treatment days. All these trials studied non-sedating
treatment
antihistamines: terfenadine, loratadine and ceterizine.
Six trials - all studying first generation antihistamines - show some (Subjective severity assessment of sneezing, non-sedating antihis-
effect. In these trials severity of sneezing was assessed in the same tamines: data of only one trial was available for each observation
way as severity of other nasal symptoms. For the description: see day, so comparisons were not possible. These trials did not show
effect on subjective severity of rhinorrhea on different treatment a significant effect)
days (Howard 1979; Turner 1997; Eccles 1995; Gwaltney 1996; Both comparisons show a significant decrease of sneezing severity
Gwaltney 1997) or effect on subjective severity of nasal obstruc- on all four treatment days (day 1: p < 0.04, other days: p < 0.001).
tion on different treatment days (Bye 1980). This effect is due to the first generation antihistamines. None

of the trials with non-sedating antihistamines show a significant (2) Participants suffering sedation (drowsiness, sleepiness, fatigue,
effect. Yet, the differences between treatment groups is small: at somnolence, sedative, dopey feeling)
most 0.31, while a difference of one would mean a difference of In eight trials, the number of participants with sedative side-
one severity category (e.g. moderate to mild). effects were registered. In total, 3389 participants were included
(ii) data not entered in the meta-analysis (see Table 6) in these eight trials: 1726 with active treatment, of which 7.9%
Data of four trials could not be entered in the meta-analysis. Two suffered sedation, 1663 with placebo of which 4.8% felt sedated.
trials (Gaffey 1988; Ectors 1994) studying non-sedating antihis- This difference is statistically significant (p = 0.0002).
tamines had no effect, two trials (Howard 1979; Bye 1980) study- When we look at trials with first generation and non-sedating an-
ing first generation antihistamines have some effect. These results tihistamines separately, we again see that sedation was more fre-
are in line with the results of the meta-analysis. quent in participants treated with first generation antihistamines:
7.9% versus 4.4% (p = 0.0001). In trials with non-sedating anti-
histamines there was virtually no difference: 8.6% versus 8% (p =
(3) Effect on other outcomes 0.9).
Doyle (Doyle 1988) interviewed 27 participants who developed a (3) Patients suffering other side-effects which are possibly more
cold after experimental virus inoculation were interviewed on days frequent with antihistamines.
three to six after inoculation. The severity scores (mild, moderate, Gastro-intestinal side-effects were reported in six trials, including
severe) obtained on these four days by interview were summed 2351 participants. With active treatment, 3.5% of participants
and averages are compared between chlorpheniramine (n = 12) suffer gastro-intestinal complaints, 2.3% with placebo (p = 0.07).
and placebo (n = 15) treated patients; a significant difference in Sleeplessness was mentioned in three trials including 1625 partic-
favour of active treatment was found (p < 0.01). In the same ipants. This is an infrequent side-effect: 1.1% with active treat-
study, the average number of days with sneezing was counted. ment, 0.2% with placebo (p = 0.06).
With chlorpheniramine there was virtually no sneezing (0.1 day In two trials, dry nose was mentioned. In one of these trials on
on average), without chlorpheniramine sneezing took on average 150 experimentally infected patients a dry feeling in the nose was
more than a day. This difference was significant (p < 0.01). very frequent (36% with clemastine versus 18 % with placebo).
In the other trial using intranasal therapy in 23 participants, a
dry nose was, on the contrary, less frequent with active treatment.
Section 5: Side effects Overall, the difference is just not significant: p = 0.06. In the trial
in which dry nose was frequent, a feeling of dry throat was also
In 17 trials side-effects were evaluated
very frequent: 33% versus 16% with placebo (p = 0.01). This is
Many different side effects are described: sedation, fatigue, sleepi-
the only trial where this side effect was mentioned.
ness, somnolence, drowsiness, lassitude, listlessness, tiredness,
(4) Patients suffering side-effects which are not more frequent with
dopey feeling, sleeplessness, insomnia, vertigo, dizziness, giddi-
antihistamines
ness, urinary complaints, dry mouth, dry nose, dry throat, dry
Frequency of headache (4 % in both treatment groups), vertigo and
eyes, headache, depression, nausea, gastric upset, muscular pain,
dizziness (3% with active and 2% with placebo) and dry mouth
temperature rise. For intra-nasal therapy, nasal burning and bleed-
(12% with active and 11% with placebo) was not significantly
ing sites in the nose are observed.
different between treatment groups.
The number of trials mentioning a certain side-effect is presented
Muscular pain, temperature rise, urinary complaints, dry eyes,
in Table 7.
nasal burning, bleeding sites in nose were all very infrequent and
Data of the different trials are pooled where possible in Data and
there is no significant difference between treatment groups.
Comparisons, comparison nr. 13.
Comparison 13
(1) Total number of patients suffering side-effects.
Eleven trials register the total number of patients with one or more Part 2: Antihistamines in monotherapy for small
side-effects. In total, 3245 participants were included in these 12 children
trials: 1653 with active treatment, of which 18.8% suffered side- Only two trials included small children and the results were con-
effects, of 1592 participants treated with placebo, 15.8% had side- flicting
effects. This difference is statistical significant (p = 0.02). Hugenin (Hugenin 1988) studied the effect of astemizole on cold
When we look at trials with first generation and non-sedating an- symptoms in 62 children from the age of two to15 years old.
tihistamines separately, we see that side-effects were only more fre- Inclusion criteria were: watery or mucous rhinorrhea, cough and
quent in participants with first generation antihistamines: 19.2% malaise. A major problem with this trial was the long duration of
versus 16.1% (p = 0.02; NNH = 32). In trials with non-sedating symptoms before inclusion (mean six days, ranging from 1 to 365).
antihistamines there was virtually no difference: 12.26 % versus Some children obviously did not have a common cold. In this trial
11.93%, p = 0.80). astemizole seems to have some effect: the number of days until

normalisation of general condition tended to be fewer with active to ten days after the start of therapy) to be improved by active
treatment (p = 0.06), and there also was a significant effect on treatment compared with placebo (p < 0.01).
rhinorrhea: the number of days until the rhinorrhea severity score Thirdly, Galvez (Galvez 1985) included 60 cold participants aged
was reduced by 50% was fewer (p = 0,001) and the proportion six years or older. Almost one fourth were lost to follow-up. Active
of children free of rhinorrhea after seven days of treatment was treatment consisted of azatadine + dextromethorphan + pseudo-
higher (p = 0.015). In these 62 children, no side-effects occurred. ephedrine. Physicians evaluated the overall therapeutic response
(All available data are summarised in Table 1 and Table 4.) after three to four days, and five to six days of treatment (exacer-
In the trial of Sakchainanont (Sakchainanont 1990) the effect of bated/poor/fair/good/excellent). At both evaluation times, there
clemastine and chlorpeniramine were studied in 150 children of was a significant difference between the total number of partici-
less then 5 years old with rhinorrhea for three days. After three pants with a favourable response (fair to excellent), in the active
days of treatment the amount of nasal discharge and the amount of treatment group and in the placebo group (p = 0.014 and p =
edema at the nasal turbinates were compared in children receiving 0.024).
active treatment or placebo. There was no significant difference Fourthly, Scavino (Scavino 1985) in a trial identical to the trial by
(p = 0.53 and 0.95 respectively) There was also no significant Galvez (1985), included 58 participants of age 6 years or older.
difference in frequency of side effects (all side effects: p = 0.80; Ten were lost to follow-up. Active treatment consisted of azata-
sleepiness/drowsiness: p = 0.64). All available data are summarised dine + dextromethorphan + pseudo-ephedrine. Participants were
in Table 5 and Table 4. evaluated by physicians after three to four and five to six days of
treatment using a five point scale. Again, at both evaluation times
the response was more favourable (fair to excellent) when active
PART 3: Antihistamines in combination therapy for treatment was compared with placebo (p = 0.010 and p = 0.012).
older children and adults Fifthly, Berkowitz (Berkowitz 1989) treated 261 participants with
In this part we will present results of trials with antihistamines in loratadine + pseudo-ephedrine or placebo. Participants kept a di-
combination with other products used for cold symptoms. First ary during the five days of treatment and were evaluated by the
we will discuss studies using a combination of antihistamines with physicians on days three and five, using a four point scale. Physi-
decongestives. In one very recent trial, an antihistamine was com- cians scores favoured active treatment at both evaluation times (p
bined with a non-steroidal anti-inflammatory drug. This study = 0.01 and p = 0.02), but participant diary scores favoured active
will be discussed separately. treatment only on day three (p = 0.02).
One trial showed no effect.
Blanco de la Mora (Blanco 2000) studied a combination of lorata-
Section 1: Global evaluation of efficacy
dine + pseudoephedrine + acetaminofen in 40 adult participants
with a common cold. Participants were evaluated on the third and
(a) Systematic review fifth day of treatment using a five-point severity score. No signifi-
cant difference was found between treatment groups.
Six trials, evaluating 594 cold episodes, assessed the global efficacy
of antihistamines in combination with oral decongestives (and
sometimes other medication) on the course of the common cold. (b) Meta-analysis
In five the combinations show some effect.
(i) Results of pooled data.
Firstly, Thackray (Thackray 1978) studied the effect of a combi-
Data of three trials are entered into a meta-analysis (Bye 1980;
nation of doxylamine + ephedrine + paracetamol + dextrometor-
Galvez 1985; Scavino 1985). All these trials use as outcome a
phan on the night symptoms of the common cold in 70 adult
comparison of the proportion of participants with beneficial ef-
participants. A crossover design was used. Participants were ran-
fects, in both treatment groups at a certain time point after start
domly divided into two groups: the first night one group took
of treatment. Still these trials are quite different from one another
placebo, the other active treatment and the second night the other
in studied populations and therapeutic combinations used.
way around. In the morning participants gave their rating of the
Following data are pooled (see Comparisons and data,
effect of the medication on their general unwell feeling (useless,
comparison nr. 14):
almost useless, not very good, good, very good, excellent): with
comparison of proportion of participants with beneficial
active treatment more participants scored the active syrup as good
effect after two to four days of treatment
to excellent compared with the placebo syrup (p < 0.05).
comparison of the proportion of participants with
Secondly, in the trial by Bye (Bye 1980), the effect of triprolidine
beneficial effect at final evaluation (Scavino 1985 : five to six
+ pseudo-ephedrine in 119 cold episodes in adult participants
days; Galvez 1985 : five to six days; Bye 1980 : eight to ten days.)
was studied. Some participants were entered several times, having
several cold episodes during the course of the study. In significantly Both meta-analyses show an effect in favour of active treatment (p
more cold episodes, participants stated at final evaluation (eight < 0.001). The number needed to treat is three for improvement

after two to four days, and three for improvement after five to ten jectively measured nasal patency but more research is necessary to
days. confirm this.
(ii) Data not entered in the meta-analysis (see Table 8).
Data from the trial by Berkowitz 1989 could not be entered in
the analysis because another type of outcome measure was used, (b) Effect on subjective severity assessments of nasal
and the trial by Thackray 1978 was also not entered because of obstruction
the crossover design. Results, however, are in line with other tri-
Seven trials assessed the effect of antihistamines with decongestives
als. Considering the trial by Blanco de la Mora (Blanco 2000) no
on the subjective severity of nasal obstruction.
numerical data are reported; this is the only trial not showing a
Two trials show no favourable treatment effect.
beneficial effect. It is not likely that results of this one limited trial
Firstly, in the trial of Virtanen (Virtanen 1983) (n = 93) partici-
would change the overall conclusion that combinations of antihis-
pants registered the mean severity score of nasal obstruction, on
tamines with decongestives have some effect on general recovery.
a four point scale (absent, mild, moderate, severe), daily for 10
days. Active treatment consisted of dexchlorpheniramine maleate
+ pseudo-ephedrine for five days. No significant differences were
Section 2: Effect on nasal obstruction
found between treatment groups (p-values not mentioned).
Secondly, Lebacq (Lebacq 1994) measured nasal patency (see ef-
fect on objectively measured nasal patency), also registered on a
(a) Effect on objectively measured nasal patency three point scale the subjective severity assessment of nasal conges-
Two trials measured changes in nasal patency in an objective way. tion: there was no difference between the three treatment groups
Firstly, Aschan (Aschan 1974a; Aschan 1974c) performed repeated (phenylpropanolamine + carbonoxamine, phenylpropanolamine
rhinometric recordings in adult volunteers with nasal blocking due + pheniramine maleate + mepyramine maleate, placebo). The chil-
to acute rhinitis, at 30 to 50 minute intervals, after one adminis- dren (6 to 12 years) in this trial (three treatment groups of six
tration of medication. He compared the effect of promethazine + children each) continued their therapy for five days and the sever-
ephedrine with placebo and of clemastine + phenylpropanolamine ity of nasal congestion was evaluated by their parents. There was
with placebo. In each comparison 30 participants were included. no significant difference between the groups (p-values were not
Increase in nasal patency was considered as a positive manomet- mentioned) on any of the treatment days. The methodological
ric change. In the first comparison, changes were positive in 10 problems of this trial were discussed previously.
out of 15 participants on active treatment; in the placebo group, In contrast with these results, five trials do show some effect.
there were none. In the second comparison the difference was even Firstly, Thackray (Thackray 1978) studied the effect of a combina-
greater: 14 /15 versus 0 /15 (p-values < 0.001). tion of doxylamine + ephedrine + paracetamol + dextrometorphan
Secondly, Lebacq (Lebacq 1994) included 36 participants (18 on the night symptoms of the common cold in 70 adult partici-
adults and 18 children aged 6 to 12 years) with acute rhinitis in or- pants, using a cross over design. The effect on nasal obstruction
der to compare the effect of placebo with (1) phenylpropanolamine was assessed in the same way as the effect on general unwell feeling
+ carbonoxamine and (2) phenylpropanolamine+ pheniramine (see global evaluation of efficac). With active treatment more
maleate + mepyramine maleate. Participants were kept under stan- participants scored the active syrup as good to excellent compared
dardised circumstances during one day and measurements were to the placebo syrup (p < 0.05).
performed at different times after one dose of medication {0.5, Secondly, in the trial by Bye (Bye 1980), the effect of tripilodine
1, 2, 4, 6.5, 11 (adults) or 10 (children) hours after medication + pseudo-ephedrine in 119 cold episodes in adult patients was
administration}. This trial has methodological problems: duration studied. Some participants were entered several times, having sev-
of symptoms before start of treatment is not clear, investigators eral cold episodes during the course of the study. Symptom sever-
were not blinded and one of the treatments was not masked (com- ity was assessed using a 4-point scale. With combination therapy,
bination 2). Moreover, allergic participants were not explicitly ex- nasal obstruction was significantly less severe on day one of active
cluded. The effect was expressed as percent of pre-treatment treatment (p-value not mentioned).
value of the nasal resistance. In the adult group, combination one Thirdly, Curley (Curley 1988) studied the effect of dexbrompheni-
had some effect on nasal resistance, until 2 hours after intake ramine maleate + pseudo-ephedrine in 86 participants. Symptom
of medication (p-values < 0.05); in children there was no effect. severity was scored on a five-point scale. Participants took medica-
Combination two was not effective. tion for seven days and completed a diary for 14 days. The mean
Pooling of these data is not possible because different outcome severity score for nasal obstruction was significantly less on days
measures were used. Results are presented in Table 9. All trials have two and three, (p < 0.01), four (p < 0.05) and five (p < 0.01).
small sample sizes and one had serious methodological problems. Fourthly, in the trial by Berkowitz (Berkowitz 1989) (n = 283)
It can, very tentatively, be concluded that some combinations of participants were evaluated by means of a four point scale on
antihistamines with decongestives might have some effect on ob- the severity of nasal obstruction during five days of therapy with

loratadine + pseudo-efedrine or placebo. From day two until day in Table 12. Of the trials with a positive effect, in only two was
five severity scores were significantly lower in the active treatment the size of this effect reported: in the trial by Berkowitz (Berkowitz
group (p-values < 0.05). 1991) the difference in mean severity score between treatment
Fifthly, Blanco de la Mora (Blanco 2000) studied a combination groups is at most 0.3 severity point (on day two of treatment),
of loratadine + pseudoephedrine + acetaminofen in 40 adult par- in the trial by Thackray (Thackray 1978), the difference in the
ticipants with a common cold. Participants were evaluated on the number of participants with favourable evaluations after intake of
third and fifth day of treatment using a five point severity score. A active treatment or placebo was 12%.
significant difference was found between treatment groups on the
third treatment day (p = 0.041).
None of these trials could be pooled because of differences in out- Section 4: Effect on sneezing
come measures or lack of adequate data. Results are summarised in Four trials assessed the effect of an antihistamine-decongestive
Table 10. Considering trials which demonstrated a positive effect, combination on the subjective severity of sneezing. For the de-
the size of this effect could only be reported in two: in the trial scription of the trials we refer to effect on nasal obstruction.
by Berkowitz, the difference in mean severity score between treat- Three show some effect.
ment groups is at most 0.3 severity point; in the trial by Thack- In the trial by Bye (Bye 1980), with combination therapy, sneezing
ray, the difference in the number of participants with favourable was significantly less severe on days two, three and four (no p-
evaluations after intake of active treatment or placebo was 24%. values mentioned).
In the trial by Virtanen (Virtanen 1983) on days two to eight, the
mean severity score of sneezing was significantly lower with active
(c) Effect on result of anterior rhinoscopia treatment (day two: p < 0.05, day three: p < 0.001, day four: p <
In the trial by Lebacq (Lebacq 1994) mentioned previously, the 0.01, day six and seven: p < 0.01, day eight: p < 0.05)
condition of the nasal mucosa was assessed at different time points In the trial by Berkowitz (Berkowitz 1989) from day two until day
using a three-point scale (normal, red, violet blue). There was no five, severity scores were significantly lower in the active treatment
difference between treatment groups. In the trial by Blanco de la group (all p-values < 0.05).
Mora (Blanco 2000), a favourable effect on oedema of the nasal One trial showed no effect.
mucosa was seen on the third treatment day (p = 0.056) (see Table In the trial by Thackray (Thackray 1978) the number of par-
11). ticipants evaluating the active syrup as beneficial compared with
Section 3: Effect on rhinorrhoea placebo, was not significantly different (p = 0.14).
Six trials assessed the effect of an antihistamine-decongestive com- The trials could not be pooled because of lack of adequate data.
bination on the subjective severity of rhinorrhoea. For the descrip- All data are presented in Table 13.
tion of the trials we refer to effect on nasal obstruction. Only one trial (Thackray 1978) reported the effect size and in-
One trial shows no favourable treatment effect. In the trial by Bye, cidence of favourable response was not significantly different be-
with combination therapy, nasal discharge was not significantly tween treatment groups.
less than with placebo (no p-values mentioned).
Five other trials showed some effect.
Section 5: Side effects
In the trial by Thackray (Thackray 1978) more participants eval-
uated the active syrup as beneficial compared with placebo (p < In 10 trials side-effect were evaluated.
0.05). Many different side-effects were described: drowsiness, hypersom-
In the trial by Virtanen (Virtanen 1983) on the third treatment nia, excessive sleepiness, dry mouth, insomnia, dizziness, palpita-
day - but not on the other nine observation days - the mean severity tions, nervousness, headache, gastro-intestinal upset and rash.
score of nasal secretion was significantly lower (p < 0.05). The number of trials mentioning a certain side-effect are presented
In the trial by Curley (Curley 1988) the mean severity score for in Table 14. Data from the different trials are pooled wherever
nasal discharge was significantly less on days two (p < 0.05) and possible in Comparison and data comparison nr. 16. Other data
three (p< 0.01). are summarized in Table 15.
In the trial by Berkowitz 1989 on day two (p < 0.05) and day
four (p < 0.05) severity scores were significantly lower in the active
treatment group. (a) Total number of patients suffering side effects
Finally, Blanco de la Mora (Blanco 2000) also found a significant In six trials, the total number of participants with one or more
reduction of rhinorrhea due to active treatment on the third treat- side-effects was registered. In total, 591 participants were included
ment day. in these six trials: 294 with active treatment, of which 80 or 27 %
Because of differences in outcome measures or lack of adequate suffered side-effects; 297 with placebo, of which 67 or 22% had
data, pooling was not possible. Available results are summarised side-effects. This difference is not statistical significant (p = 0.15).

(b) Number of participants suffering side effects that are telephone (p = 0.74). Congested or runny nose was assessed by
more frequent with combination therapy the parents by means of a four -point severity scale. There was
In three trials dry mouth is mentioned. In total 426 participants no difference between the treatment groups in terms of symptom
were included in these trials: 215 with active treatment, of which improvement (p = 0.51).
22% suffered dry mouth, and 211 with placebo, of which 24 or As to side-effects, sleeping disturbances, excessive sleepiness and
11% had this side effect. This difference is statistically significant vomiting were evaluated. Again there was no difference between
(p = 0.0003). the treatment groups (p-values > 0.2).
Clemens (Clemens 1997) also included children aged six months
to five years in a study comparing brompheniramine + phenyl-
(c) Number of participants suffering side effects that are not propanolamine to placebo in 59 children. Parents were asked to
more frequent with combination therapy evaluate the cold symptoms two hours after the intake of the med-
ication. In total, 175 responses were registered in these 59 chil-
Drowsiness or excessive sleepiness was mentioned in four trials,
dren. There was no difference in the proportion of responses re-
including 478 participants. Thirty eight participants, or 15.8 %,
porting an improvement from runny nose or nasal congestion (p =
suffered this side-effect with active treatment and 37, or 15,5%,
0.54 and 0.94 respectively), between the treatment groups. Chil-
with placebo (p = 1).
dren with active treatment were however more likely to fall asleep
Two trials - including 165 participants - mention gastro-intestinal
within two hours after the intake (p = 0.01).
side-effects: 6% with active treatment and 10% with placebo (p =
0.3).
Insomnia is also mentioned in two trials, including 334 partici-
pants: 14% with active treatment and 12% with placebo (p = 0.5).
Dizziness, rash, nervousness, headache and palpitations are all DISCUSSION
mentioned in only one trial and the incidence was not significantly
different between treatment groups.
Addendum: chlorpheniramine with ibuprofen. (1) Summary of main findings
In the recent study by Gwaltney (Gwaltney 2002), 150 partici-
pants were experimentally infected in order to investigate the effect
of a combination of antiviral-antimediator + chlorpheniramine + (a) Antihistamines in monotherapy for older children
ibuprofen. The trial had three arms: intra-nasal antiviral-antime- and adults
diator + oral chlorpheniramine + ibuprofen (n = 59), intra-nasal Antihistamines used in mono-therapy in older children and adults
placebo + oral chlorpheniramine + ibuprofen (n = 61) and intra- do not influence, in a clinically significant way, overall subjective
nasal placebo +oral placebo (n = 30). Treatment and participant improvement of the common cold, nor do they alleviate in a clin-
evaluation started 24 hours after virus challenge and lasted for five ically significant way nasal congestion, rhinorrhoea and sneezing.
days while participants were secluded and kept under close ob- On the other hand, first generation antihistamines cause more
servation. Participants evaluated their symptoms on a five-point side-effects than placebo, in particular more sedation. Looking at
scale. the pooled data of the number of patients with overall improve-
Results show that on none of the observation days was there a ment at different time periods, we see that none of the differences
difference between the placebo group and the chlorpheniramine + in number of improved patients between treatment groups ap-
ibuprofen group for baseline-adjusted mean daily scores for gen- proaches 15%, or clinical significance. Looking at individual tri-
eral malaise, nasal obstruction, rhinorrhea and sneezing. In the als, we see that only one out of 12 trials (Bye 1980) shows a sta-
treatment groups receiving an active combination, more drowsi- tistically significant difference between treatment groups of more
ness occurred (p = 0.03). than 15%. In this trial, overall subjective assessment was evaluated
in a special way, namely by asking participants once only at the
final evaluation (eight to ten days after start of therapy): After
PART 4: Antihistamines in combination therapy for small taking the trial tablets did your cold symptoms improve, worsen
children or remain unchanged? Most other trials counted the number of
Two trials evaluated the effect of a combination of antihistamines participants feeling better (from particular symptoms) during the
with a decongestive in small children. treatment course. This different approach might partly explain the
Hutton (Hutton 1991) studied brompheniramine + phenyle- difference in outcome.
phrine + phenylpropanolamine in 54 children aged six months to Considering nasal obstruction, none of the meta-analyses show
five years. Evaluation took place 48 hours after start of treatment. any beneficial effect either. With non-sedating antihistamines,
There was no difference between treatment groups in the num- nasal stuffiness is even worse after three to five days compared with
ber of parents reporting overall improvement when contacted by placebo. When the individual trials are looked at, we see only a few

with statistically significant results and, when there are sufficient versus 2.3% with placebo suffer some gastro-intestinal complaints
data to judge the effect size, it is always far less than one severity (p = 0.07). There was no difference between non-sedating and first
point. The lack of effect on nasal obstruction is not surprising, as generation antihistamines.
even in allergic patients antihistamines do not alleviate this symp-
tom (Janssens 1993).
For rhinorrhoea, we do see an effect in the meta-analyses - but only (b) Antihistamines in monotherapy for small children
from first generation antihistamines: objectively measured weight The most important finding is that very little is known about the
of expelled mucus is decreased with active therapy, and subjec- effect of antihistamines in young children. In all we only found two
tive severity scores are lower than with placebo from the second trials, which included a total of 212 children and had conflicting
treatment day on. Effect sizes are however very small: the largest results. The trial with the largest sample size, including exclusively
mean difference between the treatment groups is 0.24, which is small children (six months to five years), and using clear inclusions
highly statistically significant but much smaller than our thresh- criteria, showed no treatment effect. The other trial showed a
old for clinical significance (see Methods). Of the five trials that clear beneficial effect from treatment but it had a much smaller
could not be analysed by pooling of data, three (two using first sample size and included older children as well as small children.
generation AH, one a non-sedating AH) were negative; two others The diagnosis of cold was also unclear and some participants had
showed some effect: one with a first generation antihistamine and a very long duration of symptoms before being included. From
one using a non-sedating antihistamines but with some serious these data we can conclude that currently there is no evidence that
methodological problems (Henauer 1988). Data to evaluate the antihistamines have any effect in small children.
effect size are lacking in these trials. None of the 12 individual
trials, which studied rhinorrhoea reported an effect size approach-
ing a mean difference in severity score of one between treatment (c) Antihistamines in combination therapy for small
groups. The small decrease in rhinorrhoea is probably due to the children
inhibition of cholinergic stimulation, as this effect is solely present As to combinations of antihistamines with decongestives, we
in first generation antihistamines and not the more selective non- found again only two trials with 113 small children. Results
sedating antihistamines. showed that this therapy has no apparent effect in small children:
Findings on sneezing are very similar to those regarding rhinor- neither of the two trials indicated an greater improvement in gen-
rhoea. The meta-analyses show that first generation antihistamines eral condition, nasal obstruction, rhinorrhoea or sneezing in the
can decrease the subjectively assessed severity of sneezing in the active treatment group.
common cold. The effect size is however small (at most 0.31 less
on severity ratings) and thus hardly clinically noticeable. Of trials
not entered in these meta-analyses, two with non-sedating antihis- (d) Antihistamines in combination in older children
tamines report no effect; two with first generation antihistamines and adults
show some effect. The effect size of the individual trials - where
In older children or adults however, effect of combination ther-
reported - never reaches clinical significance.
apy on general efficacy is less clear. In the meta-analyses - which
Considering adverse effects, we found that with first generation
pooled results of three trials - we found an overall beneficial and
antihistamines side-effects are very frequent, both in the active
clinically significant effect. This must be interpreted with care for
treatment group (19%) and in the placebo group (16%). The dif-
several reasons: the sample size of the trials was small; in two there
ference, although statistically significant, is surprisingly small. Ob-
was a substantial loss to follow up; two of the trials used a combi-
viously a number of effects are attributed to the medication, but are
nation containing - apart from antihistamines and decongestives
actually cold symptoms. Non-sedating antihistamines do not cause
- an antitussive; and finally, in the trial by Bye (Bye 1980), the
more side-effects than placebo. In both treatment groups, side-ef-
overall effect was evaluated in a way -that might have influenced
fects are less prevalent with non-sedating antihistamines than with
results. Of the three trials not entered in the meta-analysis, two
first generation antihistamines. The most frequent adverse effect
also show some effect. In Berkowitz (Berkowitz 1989) (with 283
is sedation. About 8% of participants treated with first generation
participants), which was the trial with the highest methodological
antihistamines felt some sedation, versus 5% with placebo. Again
quality and the largest sample size this effect was small: only on
the number of participants feeling sedated in the placebo group is
one treatment day was there a statistically significant difference
quite large, probably because the cold itself can make people feel
between treatment groups in global rating.
fatigued. Non-sedating antihistamines, in accordance with their
Yet, five out of six trials found results in favour of active treatment,
name, do not cause more sedation than placebo. But here too a lot
so it can be tentatively concluded that combinations of antihis-
of participants report sedation for both treatment groups (8%).
tamines with decongestives have some global beneficial effect in
Many other adverse effects are mentioned. Gastro-intestinal effects
adults and older children- although results should still be inter-
are also quite frequent: 3.5% of participants with antihistamines
preted with care.

When studying the effect on cold symptoms in adults it is difficult 1994)). But, even if there are a lot of unpublished trials, they will
to come to a conclusion. The majority of trials show some relief probably have negative results and thus would not change our
on nasal obstruction, rhinorrhoea and sneezing. However in most overall conclusion.
trial reports, there was insufficient data to judge the effect size and In a number of trials, data were insufficiently reported or not in
thus the clinical significance. In two trials this was possible. One ( the right format to enter in a meta-analysis. Some authors pro-
Thackray 1978) however, evaluates specifically the effect of a single vided additional data but for many trials we did not succeed in
dose (of a combination of four different products) on the severity retrieving extra data because authors did not answer when con-
of night symptoms of the common cold and although there is a tacted, could not be located, data were no longer on file or were
clear effect, it is difficult to extrapolate this to other combinations, passed on to the sponsors of the trial. Therefore, and also because
or other times of the day. In the other trial (Berkowitz 1989) with trials showed important differences in study participants, inter-
283 participants which was of high methodological quality and ventions, outcomes or designs, we chose to make primarily a sys-
had a large sample size, the benefit was not clinically significant. tematic review rather than a meta-analysis. The performed meta-
So, while decongestives are added to antihistamines because they analyses mostly include only a part of available trials and are more
cause vasoconstriction of nasal vessels and thus potentially decrease intended as illustrations, rather than as a basis for conclusions.
nasal symptoms (Taverner 2001), it is not possible with the present In the trials, many different outcome measures were studied. We
to determine if this effect is achieved. chose firstly overall improvement because we believe this is what
patients really want when taking medication for their cold: to
feel better. Secondly, we looked at nasal obstruction, rhinorrhoea
(e) Adverse effects and sneezing because these are the most frequent cold symptoms
Adverse effects are more frequent in the active treatment groups (Jackson 1960). Cough, another important cold symptom, was
but this difference is not statistically significant. Only dry mouth not considered in this review since the effect of antihistamines
- in the trials where it is mentioned - is more frequent with active on cough has been recently reviewed in another Cochrane review
treatment when compared to placebo. (Shroeder 2001). We also did not consider changes in total nasal
Our main findings are in agreement with the conclusions of other symptom scores - which add up the subjective severity scores of
reviews (West 1975; Smith 1993; Luks 1996). West and Luks both individual nasal symptoms as an outcome measure. Some inves-
reviewed effects of antihistamines in monotherapy and both came tigators used this measure but we felt that such a total score, and
to the conclusion that there appears to be little valid evidence its changes, are difficult to understand clinically and therefore less
that antihistamines have any effect on the common cold. Smith relevant. In formulating conclusions, we did not take into account
and Feldman, reviewing trials on various over-the-counter cold effects on objective outcome measurements such as weight of ex-
medications, concluded that antihistamines in monotherapy have pelled nasal mucus, because - although these are theoretically in-
no effect on the common cold but that combination therapy, at teresting - practically they are irrelevant if not experienced by the
least in adolescents and adults, can reduce nasal symptoms, which patient as beneficial.
also agrees with our findings. However, in the review by Smith and For several comparisons in the meta-analysis, there is significant
Feldman clinical relevance of the effect size was not discussed. heterogeneity in results between studies. Two explanations are con-
sidered in the main results (difference in age of adults, adolescents
versus small children; first generation versus non-sedating antihis-
(2) Methodology tamines). Other possible reasons are: difference in the products
used within the same class of antihistamines; and difference in the
The search strategy aimed to identify any trials of treatment of the
way of infection (experimental versus community acquired colds).
common cold, from which any trials using antihistamines were
Additional Table 16, which gives a general overview of positive
selected. We searched existing databases, contacted experts and
and negative results in relation to the way of infection and the used
contacted pharmaceutical companies. There was only one restric-
product, shows that favourable results are not particularly linked
tion to the search: we did not go further back than 1950 because
to one product or to one infection way. Yet, apart from these, there
- although antihistamines have been studied since the late 1940s
are other more subtle differences between trials, in methodology,
- we considered the chances of finding trials of methodologically
in recruitment, inclusion and exclusion criteria, which maybe can
sufficient quality in that period very low. With this broad search
explain the heterogeneity of results.
strategy we are fairly confidant that we found most trials published
in the mainstream literature. Antihistamines, with or without de-
congestives, are however an important part of the OTC market
and it is likely that many studies have been performed but have not
been published, for commercial reasons. Contacting pharmaceu-
tical companies resulted in two additional trial reports (one com-
pany memo (Tebrock 1973) and one conference abstract (Ectors AUTHORS CONCLUSIONS

Implications for practice - although there were some favourable reports - no trial showed
convincingly that antihistamines really help treat the common
On the basis of this review, there is a clear case for discouraging
cold. In 1975 - after an extensive review of literature - West 1975
physicians to further prescribe antihistamines for common colds or
concluded, there appears to be little valid evidence that antihis-
for people to purchase over the counter antihistamines to alleviate
tamines have any effect on the common cold. A quarter of a cen-
their common cold symptoms : there is no evidence of clinical
tury and many trials later, we come to the same conclusion. It seems
significant effectiveness and there is a risk of side-effects, especially
very unlikely that more research on antihistamines in monother-
sedation.
apy will conclude otherwise. As to combinations of antihistamines
Combination products- containing antihistamines with decon- with decongestives, research has been less extensive and definite
gestives - should not be prescribed for small children : in both conclusions are not yet possible. It cannot be excluded that a com-
methodological valid trials comparing effectiveness of such combination of first generation antihistamines with decongestives has
binations to placebo, there was no effect. On the other hand, more some clinical relevant effect, as these histamines have some small
than 5 % of reported intoxications in children happen with cold effect nasal symptoms that might be increased by adding a decon-
medications containing such combinations (Litovitz 2000). gestive. A large trial, studying this combination might clarify this.
In adolescents and adults the situation regarding combination

products is less clear. Many trials reports beneficial effects, but in
most the effect size is not evident. In the one large trial where this ACKNOWLEDGEMENTS
information is available, effect size is too small to be clinical rele-
vant. In this trial, a combination of a non-sedating antihistamine We want to thank the following for their help: Marjan Loep who
with decongestives was studied. We have no such data from trials performed the EMBASE search; Ron dSouza who gave advice and
combining first generation antihistamines with decongestives. support as Review Group Coordinator of the Cochrane Acute Res-
piratory Infections Group and searched the Cochrane Acute Res-
piratory Infections Group trials register; Nicole Boffin who traced
Implications for research papers that were difficult to find; Keith Dear for answering some
Antithistamines in monotherapy have been studied thoroughly; statistical questions; Liz Dooley for helping with extra searches
in the last fifty years many trials have been performed in different and with the final preparation of the review; and all authors who
settings, with different products and on different populations and were kind enough to send us additional data.
REFERENCES
References to studies included in this review Berkowitz 1991 {published data only}
Berkowitz RB, Tinkelman DG. Evaluation of oral
terfenadine for treatment of the common cold. Annals of
Aschan 1974a {published data only} Allergy 1991;67:5937.

Aschan G. Decongestion of nasal mucous membranes
by oral medication in acute rhinitis. Acta Otolaryngologica Blanco 2000 {published data only}
1974;77:4338. Blanco de la Mora E, Carrillo L, Barrera Marky de
la B. Efficacy and safety of loratadine, pseudoefedrine
Aschan 1974b {published data only} and acetaminophen in the non-sedating symptomatic
Aschan G. Decongestion of nasal mucous membranes by treatment of the common cold [Eficacia y seguridad de
oral medication in acute rhinitis. Acta Otolaryngologica laratadine, pseudoefedrina y acetaminofn en el tratamiento
1974;77:4338. sintomtico no sedante del resfriado comn]. Investigacin
Mdica Internaciaonal 2000;27:1425.
Aschan 1974c {published data only}
Aschan G. Decongestion of nasal mucous membranes by Bye 1980 {published data only}
oral medication in acute rhinitis. Acta Otolaryngologica Bye CE, Cooper J, Empey DW, Fowle ASE, Hughes DTD,
1974;77:4338. et al.Effects of pseudoefphedrine and triprolidine, alone and
in combination, on symptoms of the comon cold. BMJ
Berkowitz 1989 {published data only}
1980;281(6234):18990.
Berkowitz RB, Connell JT, Dietz AJ, Greenstein SM,
Tinkelman DG. The effectiveness of the nonsedating Clemens 1997 {published data only}
antihistamine loratadine plus pseudo-ephedrine in the Clemens CJ, Taylor JA, Almquist JR, Quinn HC, Mehta A,
symptomatic management of the common cold. Annals of Naylor GS. Is an antihisamine-decongestant combination
Allergy 1989;63:3369. effective in temporarily relieving symptoms of the common
cold in preschool children?. Journal of Pediatrics 1997;130: fumarate for treatment of experimental rhinovirus colds.
4636. Clinical Infectious Diseases 1996;22:65662.
Cowan 1950 {published data only} Gwaltney 1997 {published and unpublished data}
Cowan DW, Diehl HS. Antihistaminic agents and ascorbic Gwaltney JM, Druce HM. Efficacy of brompheniramine
acid in the early treatment of the common cold. JAMA maleate for the treatment of rhinovirus colds. Clinical
1950;143(5):4214. Infectious Diseases 1997;25:118894.
Crutcher 1981 {published data only} Gwaltney 2002 {published data only}
Crutcher JE, Kantner TR. The effectiveness of Gwaltney JM Jr, Winther B, Patrie JT, Hendley JO.
antihistamines in the common cold. Journal of Clinical Combined antiviral-antimediator treatment for the
Pharmacology 1981;21:915. common cold. Journal of Infectious Diseases 2002;186(2):
Curley 1988 {published data only} 14754.
Curley FJ, Irwin RS, Pratter MR, Stivers DH, Doern GV, Henauer 1988 {published data only}
Vernaglia PA, et al.Cough and the common cold. American Henauer SA, Clck U. Efficacy of terfenadine in the
Review of Respiratory Disease 1988;138:30511. treatment of common cold. A double-blind comparison
Doyle 1988 {published data only} with placebo. European Journal of Clinical Pharmacology
Doyle WJ, McBride TP, Skoner DP, Maddern BR, Gwaltney 1988;34:3540.
JM, Uhrin M. A double-blind, placebo-controlled clinical Howard 1979 {published data only}
trial of the effect of chlorpheniramine on the response of the Howard CJ, Kantner TR, Lilienfield LS, Princiotto JV,
nasal airway, middle ear and eustachian tube to provocative Krum RE, Crutcher JE, et al.Effectiveness of antihistamines
rhinovirus challenge. Pediatric Infectious Disease Journal in the symptomatic management of the common cold.
1988;7:21542. JAMA 1979;242(22):24147.
Eccles 1995 {published and unpublished data} Hugenin 1988 {published data only}
Eccles R, Van Cauwenberge P, Tetzloff W, Borum P. A Hugenin M, Martin Du Pan R, Oppikofer-Doody A-M.
clinical study to evaluate the efficacy of the antihistamine Astemizole in the treatment of acute rhinopharyngitis
doxylamine succinate in the relief of runny nose and (common cold). Double blind study in pediatrics.
sneezing associated with upper respiratory tract infection. [LAstmizole dans le traitement de la rhinopharyngite aigu
Journal of Pharmacy and Pharmacology 1995;47:9903. (common cold). Etude en double aveugle en pdiatrie.].
Ectors 1994 {published data only} Revue Medicale de la Suisse Romande 1988;108:9616.
Ectors L, Van Cauwenberghe P. Effectiveness of Hutton 1991 {published data only}
antihistamine cetirizine in the symptomatic treatment Hutton N, Hoover Wilson M, Mellits ED, Baumgarter
of rhinovirus-induced common cold. XV Congress of R, Wissow LS, Bonucelli C, et al.Effectiveness of an
European Rhinological Society and XIII International antihistamine-decongestant combination for young children
Symposium of Infection and Allergy of the Nose. with the common cold : a randomized, controlled clinical
Copenhagen, 1994:Abstract 265. trial. Journal of Pediatrics 1991;118:12330.
Gaffey 1987a {published data only} Lebacq 1994 {published data only}
Gaffey MJ, Gwaltney JM, Sastre A, Dressler WE, Correntine Lebacq E Jr, Gline JP, Joue P, Stockis A, Calderon P, Van
JV, Hayden FG. Intranasally and orally administered Schoor O, et al.Exploratory study of the decongestive effect
antihistamine treatment of experimental rhinovirus colds. of rhinopront syrup in adults and in children with acute
American Review of Respiratory Disease 1987;136:55660. rhinitis. Clinical Trials and Meta-analysis 1994;29:11324.
Gaffey 1987b {published data only} Lorriman 1950 {published data only}
Gaffey MJ, Gwaltney JM, Sastre A, Dressler WE, Correntine Lorriman G, Martin WJ. Trial of antistin in the common
JV, Hayden FG. Intranasally and orally administered cold. BMJ 1950;August 19:4301.
antihistamine treatment of experimental rhinovirus colds. MRC (Part II) 1950 {published data only}
American Review of Respiratory Disease 1987;136:55660. Medical Research Council. Clinical trials of antihistaminic
Gaffey 1988 {published and unpublished data} drugs in the prevention and treatments of the common
Gaffey MJ, Kaiser DL, Hayden FG. Ineffectiveness of oral cold. Part II : large -scale thrapeutic field trial. BMJ 1950;
terfenadine in natural colds : evidence against histamine as August 19:42530.
a mediator of common cold symptoms. Pediatric Infectious Muether 2001 {published data only}
Disease Journal 1998;7(3):21542. Muether PS, Gwaltney JM. Variant effect of first and second
Galvez 1985 {published data only} generation anthistamines as clues to their mechanism of
Galvez J. Symptomatic treatment of patients with the action on the sneeze reflex in the common cold. Clinical
common cold. Clinical Trials Journal 1985;22(6):48997. Infectious Diseases 2001;33:14838.
Gwaltney 1996 {published and unpublished data} Sakchainanont 1990 {published data only}
Gwaltney JM Jr, Park J, Paul RA, Edelman DA, OConnor Sakchainanont B, Chantarojanasiri T, Ruangkanchanasetr
RR, Turner RB. Randomized controlled tial of clemastine S, Tapasart C, Suwanjutha S. Effectiveness of antihistamines
in common cold. Journal of the Medical Association of Mc Laurin 1966 {published data only}
Thailand 1990;73(2):96101. McLaurin JW, Graves TA, Komet H. Efficacy of Actifed as
Scavino 1985 {published data only} decongestant. Laryngoscope 1966;76:16124.
Scavino Y. Combination therapy in patients with the McCormick 1996 {published data only}
common cold. Current Therapeutic Research 1985;38(5): McCormick DP, John SD, Swischuk LE, Uchida T. A
74654. double-blind, placebo-controlled trial of decongestant -
Tebrock 1973 {unpublished data only} antihistamine for the treatment of sinusitis in children.
Tebrock HE. A multi-Center study of the antitussive efficacy Clinical Pediatrics 1996;35(4):45760.
of benylin expectorant in the common cold. Unpublished McGuiness 1976 {published data only}
data, Parke-Davis (Protocol 266-17) 1973. McGuiness BW. Trial of a long-acting antihistamine in
Thackray 1978 {published data only} the treatment of coryza. British Journal of Clinical Practice
Thackray P. A double-blind, crossover controlled evaluation 1976;30:156.
of a syrup for the Night-Time relief of the symptoms of the Meurman 1975 {published data only}
common cold, containing paracetamol, dextromethorphan Meurman OH, Rantanen T. A controlled clincial
hydrobromide, doxylamine succinate and ephedrine comparison of nasal decongestants in acute rhinitis. Journal
sulphate. Journal of International Medical Research 1978;6: of International Medical Research 1975;3:35662.
1615.
Middleton 1981 {published data only}
Turner 1997 {published data only}
Middleton RSW. Double blind trial in general practice
Turner RB, Sperber SJ, Sorrentino JV, OConnor R, Rogers
comparing the efficcy of benylin day and night and
J, Batouli AR, et al.Effectiveness of Clemastine fumarate for
paracetamol in the tredatment of the common cold. British
treatment of rhinorrhea and sneezing associated with the
Journal of Clinical Practice 1981;35:297300.
common cold. Clinical Infectious Disease 1997;25:82430.
MRC (Part 1) 1950 {published data only}
Virtanen 1983 {published data only}
Medical Research Council. Clinical trials of antihistaminic
Virtanen H. A slow release combined preparation
drugs in the prevention and treatment sof the common
(dexchlorpheniramine + pseudoephedrine) for symptomatic
cold. Part I : the prophylactice experiment at Salisbury.
treatment of the common cold. Journal of Laryngology and
BMJ 1950;August 19:42530.
Otology 1983;97:15963.
Riu 1976 {published data only}
References to studies excluded from this review Riu. Actifed in ENT. Clinical, rhinometric an audimetric
study [Actifec en O.R.L. Etude clinique, rhinorheometrique
Jaff 1983 {published data only}
et audiometrique]. Cahiers dO.R.L. 1976;11(7):6238.
Jaff G, Grimshaw JJ. Randomized single-blind trial in
geral practice comparing the efficacy and palatability of US NAVY 1950 {published data only}
two cough linctus preparations, pholcodix and Actifed Personnel of United States Naval Medical Research Unit
Compound, in children with acute cough. Current Medial nr 4. The prophylaxis and treatment of acute respiratory
Research and Opinion 1983;8(8):5949. diseases with antihistaminic drugs. Prophylactic treatment
in navy male recruits. 1950:55569.
Jansen 1983 {published data only}
Jansen W. Double-blind comparison of azatadine maleate/ Weippl 1984 {published data only}
pseudoephedrine sulphate syrup with placebo in relieving Wieppl G. Therapeuritic approaches to the common cold
symptoms of the common cold. Clinical Trials Journal in children. Clinical Therapeutics 1984;6(4):47582.
1983;20(5):290301.
Additional references
Kaminszczik 1983 {published data only}
Kaminszczik I, Barbon L. Relieving symptoms of upper Jackson 1958
respiratory allergies and the common cold : azatadine Jackson GG, Dowling HF, Spiesman IG, Boand A.
maleate/pseudoefedrine sulfate syrup versus placebo. Transmission of the common cold to volunteers under
Journal of International Medical Research 1983;11:1017. controlled conditions. I. The common cold as clinical
Lea 1984 {published data only} entity. AMA Archives of Internal Medicine 1958;101:
Lea P. A double-blind controlled evaluation of the nasal 26778.
decongestant effect of Day Nurse in the common cold. Jackson 1960
Journal of International Medical Research 1984;12:1247. Jackson GG, Dowling HF, Anderson TO. Susceptibility
Maranta 1996 {published data only} and immunity to common upper respirtory viral infections
Maranta CA, Simmens D. Decongestant nasalspray. Results - the common cold. Annals of Internal Medicine 1960;53:
of rhinomanometric double blind study [Abschwellende 71938.
nasal spray. Ergebenisse einer rhinometrische objectivierten, Jadad 1996
doppelblind durchgefuhrten study]. Schweizerische Jadad AR, Moore RA, Carrol D, Jenkinson C, Reynolds
Medizinische Wochenschrift 1996;126:187580. JM, Cavaghan DJ, et al.Assessing the quality of reports

on randomized clinical trials : Is blinding necessary?. NIAID 2001
Controlled Clinical Trials 1996;17:112. National Institutes of Health. National Institute of Allergy
and infectious diseases. NIAID Facts Sheets. The common
Janssens 1993
cold. http://www.niaid.nih.gov:factsheets:cold.htm. 2001.
Janssens M ML, Howarth PH. The antihistamines of the
nineties. Clinical Reviews in Allergy 1993;11:11153. Shroeder 2001
Schroeder K, Fahey T. Over-the-counter medications for
Litovitz 2000 acute cugh in children and adults in ambulatory settings.
Litovitz TL, Klein-Schwarz W, White S, Cobaugh DJ, Cochrane Database of Systematic Reviews 2001, Issue 4.
Youniss J, Omslaer JC, et al.2000 Annual report of [DOI: 10.1002/14651858.CD001831.pub3]
the American Association of Poison Control Centers.
Toxic Exposure Surveillance System. American Journal of Smith 1993
Emergency Medicine 2001;19:33795. Smith MB, Feldman W. Over-the-counter cold medications.
A critical review of clinical trials between 1950 and 1991.
Luks 1996 JAMA 1993;269:225863.
Luks D, Anderson MR. Antihistamines and the common Welliver 1990
cold. A review and critique of the literature. Journal of Welliver RC. The role of antihistamines in upper respiratory
General International Medicine 1996;11:2404. tract infections. Journal of Allergy and Clinical Immunology
Nacleiro 1988 1990;86:6337.
Nacleiro RM, Proud D, Kagey-Sobotka A, Lichtenstein LM, West 1975
Hendley JO, Gwaltney JR. Is histamine responsible for the West S, Brandon B, Stolley P, Rumrill R. A review of
symptoms of rhinovirus colds? A look at the inflammatory antihistamines and the common cold. Pediatrics 1975;56:
mediators following infection. Pediatric Infectious Diseases 1007.

Journal 1988;7:21542. Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Aschan 1974a
Methods A. SF 11 J 1-2-1
b.RCT double blind placebo controlled
c.natural colds
d.30 patients included
e.100% follow-up
Participants -adult volunteers

-setting: university department, recruitment: not clear
-inclusion: nasal blocking due to acute rhinitis
-exclusion: complications (patients with history of pollen allergy not excluded, test were performed in
season without pollen)
-duration of symptoms before inclusion: 2 to3 days
Interventions promethazine chloride 15 mg+ efedrine 10 mg

duration : 1 administration
Outcomes rhinomanometric changes in nasal patency

(positive of negative change)
Notes
Risk of bias
Item Authors judgement Description
Allocation concealment? Yes A - Adequate
Aschan 1974b
Methods a. SF 11 J 1-2-1
c.natural colds
d. 30 patients included
e. 100% follow-up30

-inclusion: nasal blocking due to acute rhinitis -exclusion: complications (patients with history of pollen
allergy not excluded, test were performed in season without pollen)
Interventions clemastine 1 mg
duration : 1 administration

Aschan 1974b (Continued)

Notes
Risk of bias
Aschan 1974c
c.natural colds
e.100% follow up

-inclusion: nasal blocking due to acute rhinitis
-exclusion: complications (patients with history of pollen allergy not excluded, test were performed in
season without pollen)
Interventions clemastine 1 mg + phenylpropanolamine 50 mg retarded

duration: 1 administration

Notes
Risk of bias

Berkowitz 1989
Methods a. SF 12/13 J 2-2-1

b. RCT double blind placebo controlled
c. natural colds
e.92% follow-up
Participants -adult volunteers -setting: multicenter trial, recruitment: not clear

-inclusion: moderate rhinorrhea and stuffiness and a minimum sum score (on 4 point scale) of at least
5 for subjective symptoms (nasal discharge, nasal congestion, sneezing, post-nasal drip, cough, earache,
sore throat, eye watering/tearing) and at least 5 on physical signs (nasal airway patency, eye redness, nasal
hyperemia, rhinorrhea, mucosal swelling)
-exclusion: fever, exudative tonsillitis, symptoms of allergy, asthma, eczema, and sinusitis; use of concomi-
tant medications including steroids, cromolyn, antibiotics, or other cold preparations; negative strepto-
coccal screening and pregnancy test
-duration of symptoms before inclusion: 48 h
Interventions loratadine 5mg /pseudoefedrine 120 mg 2x/d

duration of therapy : 5 days
Outcomes 1.overall response according to physician on day 3 and 5

2. severity score of different signs on day 3 and 5 evaluated by physicians (rhinorrhoea, patency, swelling*
)
3. daily overall response score by patients
4. daily severity score of different symptoms by patients (nasal stuffiness, nasal discharge, sneezing e.a.)
5. side effects
Notes
Risk of bias
Berkowitz 1991
Methods a. SF11 J1-2-1

c. natural colds
e. 97% follow-up
Participants -age 12 to65

-setting: allergy clinic, recruitment: not clear
-inclusion: sudden onset of symptoms of common cold with runny nose or stuffy nose rated as moderate
or severe, and at least one other symptom (sniffles, sneezing, postnasal drip, cough and/or sore, scratchy
or itchy throat)
-exclusion: smoking, fever > 100 F, exudative pharyngitis, diagnosed with perennial rhinitis, pregnancy,
lactation, intake of antihistamines, decongestants, decongestant nasal sprays, cold preparations, corticos-

Berkowitz 1991 (Continued)
teroids, antibiotics within 24 h of enrolment, use of depot corticosteroid within 8 weeks of enrolment -
duration of symptoms before inclusion : 6 to 48 h
Interventions terfenadine 60 mg 2x/d

duration : 4 days
Outcomes 1.severity score of runny nose, stuffy nose, sneezing e.a. after 4 days of treatment
2.physicians evaluation of global effectiveness
Notes
Risk of bias
Blanco 2000
c. natural colds
e. 100% follow up
Participants -age: 18-45-setting: hospital research center

-inclusion: at least 12 on the sum of symptom scores (0 to 3) for rhinorrhea, nasal congestion, nasal
itch, general malaise, odynohagia, headache conjunctival hyperaemia, lacrimation + at least 5 on the sum
of symptom scores (0 to 3) for nasal mucosal oedema, retronasal discharge, conjunctival hyperaemia,
obstruction of right and left nostrils. -exclusion: preceding of present evidence of suffering allergies and/
or bacterial infections
- duration of symptom before inclusion : 48 h
Interventions loratadine 2.5 mg + pseudoephedrine 60mg + acetaminophen 500 mg

2 tablets every 12 hours
duration : 5 days
Outcomes 1.severity assessment by the investigators on a 5 point scale of nasal congestion, rhinorrhea and general
malaise e.a. on day 3 and 5 of treatment
2.patients self-evaluation of symptoms
3.evaluation of drowsiness
Notes
Risk of bias

Blanco 2000 (Continued)
Bye 1980
c. natural colds
d. 180 colds occurring in ? patients
e.97% follow-up
Participants -adults
-setting: multicenter, recruitment : volunteers of staff of 4 divisions of a pharmaceutical company
-inclusion : healthy adults - enrolled before symptoms - developing symptoms of cold during study period
-exclusion : other medication with possible interference in study, allergic disorders
-duration of symptoms before start therapy : average 20 h
Interventions -triprolidine 2.5 mg 3x/d

-triprolidine 2.5 mg + pseudoefedrine 60mg 3x/d
duration of treatment : as long as necessary (maximal 20 tablet or 7 days)
Outcomes 1. daily scores (4 point scale) of runny nose, sneezing, blocked nose
2. daily sore of 7 possible side effects
3. overall assessment 8 10 days after start of treatment
Notes unit of analysis is number of colds, not patients (some patients have more than one cold entered)
Risk of bias
Clemens 1997
c. natural colds
d. 175 responses in 59 children
e. follow-up : unclear
Participants -age : 6 mo - 5 yr
-setting : 4 private pediatric practices, recruitment : children presenting at these clinics
-inclusion: diagnosis of URTI
-exclusion: history of asthma or allergies, currently or subsequently taking any prescribed medication
-duration of symptoms before therapy : < 7 d

Clemens 1997 (Continued)
Interventions -brompheniramine maleate 2mg/5ml and -phenylpropanolamine hydrochloride 12.5mg/5ml

dose : 6m0-2yr half a teaspoon, 2-5yrs : 1 teaspoon (as-needed,max every 4 hours)
Outcomes during 48 hours - 2 hours after each intake of medication - registration of :

1. proportion of patients with improvement on runny nose, nasal congestion *
2. severity scores of runny nose, nasal congestion *
Notes unit of analysis is response not treated child.
Risk of bias
Cowan 1950
Methods a.SF 7 J 1-0-1

b. RCT : placebo controlled (single/double?) blind
c. natural colds
d. 595 colds occuring in 219 patients
e. 85.4% follow-up
Participants -age: young adults

-setting: university, recruitment: student volunteers, enrolled before symptoms, treatment starts immedi-
ately after naturally occurring cold.
-inclusion: onset of cold
-exclusion : not clear (patients with allergy were afterwards removed)
-duration of symptoms before inclusion : immediately after onset of symptoms
Interventions phenidramine tartrate 25 mg 1x/4h

tripenlennamine hydrochloride 50 mg 1x/4h
duration of treatment 2.5 days or 10 doses
Outcomes 1. proportion of colds lasting less than 4 days

2. proportion of colds lasting only 1 or 2 days
3. side effects
Notes 1. not clear if distributors of medication and efficacy assessors were blind
2.allocation by rotation
3.unit of analysis is cold, not student - several student entered study more than once
Risk of bias
Allocation concealment? No C - Inadequate

Crutcher 1981
Methods a.SF 11 J 1-2-1

b.RCT placebo controlled double blind
c. natural colds
d.106 patients enrolled
e.91.5% follow-up
Participants -adults
-setting: department of family medicine, recruitment: not clear; patients kept under observation
-inclusion : symptom score of at least 6 (scoring system: sore throat, runny stuffy nose, sneezing, PND,
cough (0-3)
+ 2.signs score (physical examination) of at least 5: nasal swelling, nasal redness, nasal secretion, obstruction
right nostril, obstruction left nostril (0-3)
-exclusion criteria: fever, exsudative tonsillitis, allergy, asthma, eczema, sinusitis, use of steroid, antibiotics
or other cold medication (aspirin was allowed)
-duration of symptoms before inclusion: <=48 h
Interventions chlorpheniramine maleaat 4 x /d

duration of treatment: 7 days
Outcomes 1. overall assessment of severity of current symptoms compared to start of cold at different times
2. severity score of drowsiness
3. open ended questions about side effects
Notes
Risk of bias
Curley 1988
b. RCT placebo controlled double blind
c. natural colds
e.85% follow up
Participants -adults > 18 yr

-setting: university hospital, recruitment: unclear - patients kept under observation
-inclusion: symptoms and physical signs of nasal passages (e.g. rhinorrhea, sneezing, nasal obstruction).
-exclusion: pregnancy; intake of aspirin, analgesic, antihistamines, decongestants, antibiotics in prior 48
h; known allergy or vasomotor rhinitis, asthma, eczema, chronic sinusitis, obstructive pulmonary disease;
oral temp > 38 ; suggestion of allergic or vasomotor rhinitis, sinusitis, pneumonia, acute non respiratory
illness, positive throat culture for BHSGA, broncho provocation consistent with symptomatic asthma
duration of symptoms before inclusion : 12 to 72 h

Curley 1988 (Continued)
Interventions 6 mg dexbrompheniramine maleate + 120 mg pseudo-efecrine sulfate 2x/d

duration of treatment : 1 week
Outcomes 1.daily subjective severity scores of different symptoms (nasal obstruction, nasal discharge, sneezing*)
2.prevalence of different symptoms 14 days after start treatment (nasal obstruction, nasal discharge,
sneezing*
Notes
Risk of bias
Doyle 1988
c. experimental virus colds
d. 40 inoculated, 27 colds
e. follow-up 100%
Participants -age: adults

-setting: experimental, recruitment by advertisements - patients kept under observation
-inclusion: patient developing a cold after inoculation (cold = total sum score of 6 or more from days
2 tot 6 (symptoms scored on 3 point scale : sneezing, headache, malaise, chilliness, nasal discharge, nasal
congestion, sore throat)) and either rhinorrhea for more than 3 days or believed they had a cold.
-exclusion: allergy, systemic disease, elevated antibody titre against used type of rhinovirus.
-duration of symptoms before inclusion : therapy start day 2 after inoculation
Interventions chlorpheniramine 4mg/4h,

duration : from day 2 (evening) until day 7
Outcomes 1.daily measurement of nasal airway patency

2.daily measurement of expelled nasal mucus weights
3.symptom scores (sum of scores over treatment days)
4.mean duration of different symptoms (nasal congestion, rhinorrhoea, sneezing *)
Notes
Risk of bias

Eccles 1995
c. natural colds
e. follow-up 100%

-setting: multicenter study, recruitment by advertisements
-inclusion: history of common cold with runny nose (scores 1 or more on 5-point scale) and at least 1
other symptom (blocked nose, sore throat, cough, headache, sneeze) + 0.2 gr or more nasal secretion after
15 minutes without nose blowing.
-exclusion: perennial allergic rhinitis on history, excerbation of seasonal allergic rhinitis, any systemic
disease which may have compromised respiratory function
-duration of symptoms before inclusion : at most 72 hours.
Interventions doxylamine succinate 7.5 mg/10 ml syrup 4/d

duration of treatment : 2.5 days (9 doses)
Outcomes 1.median subjective symptom score on day 2 for runny nose and sneezing
2. side effects
Notes
Risk of bias
Ectors 1994
Methods a. only abstract available - insufficient information for quality assessment

b. RCT placebo controlled double-blind
c. experimental infections
d. 40 patients
e. 100% follow-up

-setting: university department of ENT, recruitment : not clear; patients kept under observation
-inclusion: healthy volunteers, developing a cold after virus inoculation (cold = sum of symptom scores
of sneezing, rhinorrhea and nasal congestion is 4 or more)
-exclusion: known allergy
-duration of symptoms before start of treatment : treatment started immediately after onset of cold
Interventions cetirizine 5 mg 2x/d

duration of treatment : unclear

Ectors 1994 (Continued)
Outcomes 1.decrease in severity score of rhinorrhoea, nasal congestion, sneezing between start treatment and day 2
2.decrease in weight of nasal secretions between start treatment and day 2
Notes
Risk of bias
Allocation concealment? Unclear B - Unclear
Gaffey 1987a
d. 23 volunteers included
e. 100% follow-up
Participants - adults (male) volunteers

-setting : university department; recruitment : not clear - patients kept under observation
-inclusion : healthy - AB titer rhinovirus type 39 <= 1:2
-exclusion : URTI or fever of unknown origin within 1 wk before study; concurrent use of orally or
intranasally administered medications, history of atopy, sinusitis, asthma, chronic rhinitis, chronic medical
illness
-duration of symptoms before inclusion : treatment started 24 h after inoculation
Interventions intranasally diphenhydramine (0.5mg%, 100 microgram per dosis, 2 doses 4 times a day)
duration of therapy : 5 days
Outcomes 1.nasal mucus weight

2.nasal tissue count
3. side effects
Notes treatment started in all inoculated patients before start of symptoms

only 17 of the 23 patients developed a cold - but all patients were evaluated
Risk of bias

Gaffey 1987b
d. 21 volunteers included
e. 100% follow-up
Participants -adults (male) volunteers, experimentally infected,

- setting : multicenter experiment - university departments; recruitment not clear - patients kept under
observation.
-inclusion : healthy - AB titer rhinovirus type 39 < 1:24.
-exclusion: URTI or fever of unknown origin within 1 wk before study, concurrent use of orally or
intranasally administered medications, history of atopy, sinusitis, asthma, chronic rhinitis, chronic medical
illness
patients were kept under observation during 5 days
-duration of symptoms before inclusion: treatment started 24 h after inoculation
Interventions chlorpheniramine 4 X 4 mg
duration : 4 days.
Outcomes 1.nasal mucus weight

2. nasal tissue count
3. side effects
Notes treatment started in all inoculated patients before start of symptoms

only 14 of the 21 patients developed a cold - but all patiens evaluated
Risk of bias
Gaffey 1988
c. natural colds
d. 250 patients enrolled
e.94 % follow up
Participants - age: adults

- setting: university hospital, recruitment : unclear
- inclusion: recent cold with runny or stuffy nose, and 1 other respiratory symptom (sniffles, sneezing,
PND, cough, sore throat)
-exclusion: fever, exsudative pharyngitis, history of atopy, AH or other cold therapy in previous week
-duration of symptoms before inclusion : 6 to 48 h

Gaffey 1988 (Continued)
Interventions terfenadine 60mg 2X/d

duration of therapy : 3,5 days (6 doses)
Outcomes 1. symptoms scores (runny nose, stuffy nose, sneezing *) at different times
2. global evaluation (proportion of patients with complete or marked symptom relief at conclusion of
study
3. side effects
Notes
Risk of bias
Galvez 1985
c.natural colds
e. 76.6 % follow-up on efficacy , 86% for safety evaluation
Participants -6 years or older

-setting : not clear, recruitment: not clear
- inclusion criteria : minimum total symptom score of 8 for rhinorrhoea, nasal congestion, cough, sneezing,
postnasal drip, lacrimation (scored on 4 point scale); at least mildly severe nasal congestion, rhinorrhoea and
cough (score 1 or more for each);minimum total sign score of 4 (swelling and hyperaemia of nasopharygeal
mucosa, nasal secretions and obstruction of the left and right nostrils, scored on 4 point scale)
-exclusion criteria : pregnancy and lactation; known hypersensitivity to study medication; renal, hepatic,
serious cardiovascular disease, hypertension, arrhythmias, hyperthyroidism, peptic ulcer, pyloroduodenal
obstruction, glaucoma, predisposition to urinary retention, prostatic hypertrophy, asthma or a history of
asthma, allergic respiratory disease or other serious illness, concomitant pulmonary, nasopharygeal or sinus
bacterial infection including exudative pharyngitis; purulent nasal secretions, severe sore throat (score >3)
or temperature > 37.8); use of corticosteroids within past 5 days (orally), past 3 weeks (parenteral) or past
2 weeks (intranasal);use of MAO inhibitors;12 hour wash out of cold medication, aspirin and antibiotics
-duration of symptoms before entry : 24 to 48 h
Interventions SHC 399 syrup (1 mg azatadine maleate, 60 mg pseudo efedrine sulphate, 20 mg dextromethorphan
hydrobromide / 5 ml) 1 teaspoon 3 x / d (< 12 yr 1/2 teaspoon)
duration of treatment : 5 days
Outcomes Sum score at day 3 and 5 of:

1. overall therapeutic response (proportion of patients with excellent or good response)
2. side effects
Notes

Galvez 1985 (Continued)
Risk of bias
Gwaltney 1996
c. experimental colds
e. 99.3% follow-up

-setting: university, multicentre; recruitment: not clear - patients kept under observation
-inclusion: healthy volunteers, experimentally inoculated with cold virus and developing at least one mild
to moderate cold symptom 60 h or less after inoculation (sneezing, rhinorrhea, nasal obstruction, sore
throat, cough, headache, malaise, chilliness)
-exclusion: neutralising AB >1:2 against inoculated virus, colds or fever >100F 2 weeks before entering,
history of hypersensivity against antihistamines, history of allergic rhinitis, bronchial asthma, lower respi-
ratory tract disease (COPD, emphysema), use of AH, cough / cold medication thought to interfere with
study medication, MAO inhibitors within 7 days before start of the study ; subjects were screened for
alcohol, drugs abuse and tobacco during 6 months before entering the study, pregnancy and lactation,
poorly controlled hypertension, heart disease, hyperthyroidea, nasal abnormalities - other medical condi-
tions that might alter absorption, distribution, metabolism, excretion of the study drug
-duration of symptoms before start of treatment : treatment starts 24 - 48 h after virus challenge
Interventions clemastine fumarate 1.34 mg 2x/d

duration : start at earliest 24h after challenge (later if symptoms developed later) during 4 days
Outcomes 1. symptoms severity score : sneezing, rhinorrhea, nose obstruction*

2. daily nasal secretion weights
3. daily sneeze counts
4. global evaluation
5.adverse effect : frequency of dry nose, dry throat, dry mouth
Notes
Risk of bias

Gwaltney 1997
e. 85 %follow-up
Participants -age: > 18 yr,

-setting: university, recruitment: unclear, patients kept under observation
-inclusion: healthy volunteers, experimentally inoculated with cold virus and developing at least one mild
to moderate cold symptom 60 h or less after inoculation (sneezing, rhinorrhea, nasal obstruction, sore
throat, cough, headache, malaise, chilliness)
-exclusion : neutralising AB >1:2 against inoculated virus, colds or fever >38c 2 weeks before entering
, history of allergic rhinitis, bronchial asthma, use of AH, cough / cold medication within 48 h of virus
challenge, hismanal within 30 days prior to virus challenge, MAO inhibitors prior 7 days, excessive use
of alcohol, drugs abuse and tobacco during 6 months before entering the study, pregnancy and lactation,
difficult urination, glaucoma; intake of any other current medication except oral contraceptives
-duration of symptoms before start of treatment: treatment starts 24 - 48 h after virus challenge
Interventions brompheniramine12 mg 2x/d

duration : 4 days
Outcomes 1. daily nasal secretion weight

2. daily sneeze counts
3.daily symptom severity score : rhinorrhea, sneezing, nasal obstruction*
4. final global improvement score
5.side effects
Notes
Risk of bias
Gwaltney 2002
e. 100% follow-up
Participants -age : 18-51

-setting : university research center; recruitment not clear; patients kept under observation
-inclusion: healthy volunteers, experimentally inoculated with cold viruses
-exclusion : pregnancy, cold symptoms in the 2 weeks before virus challenge, history of allergic rhinitis,
bronchial asthma, chronic sinusitis, chronic lung disease, allergy to study medication

Gwaltney 2002 (Continued)
-treatment starts 24 hours after inoculation
Interventions study with 3 arms: for this review we look at results of comparison between group 2 and 3.
2.ibuprofen 400 mg +chlorpheniramine 12 mg
1/12 h + intranasal placebo spray
3. placebo oral medication + placebo intranasal spray 1/12 h
duration : 4,5 days
Outcomes 1. comparison of base-line adjusted total symptom score on day 2 until 5 of treatment
2. comparison of base-line adjusted severity scores of nasal congestion, sneezing, nasal obstruction and
general malaise on day 2 until 5 of treatment
3.comparison of weight of nasal secretion
Notes not all patients were infected or developed symptoms of common cold
Risk of bias
Henauer 1988
Methods a. SF 11, J 1-1-1

c. natural colds
d. all patients 91, eligible 63
e. 99%
Participants -age : adults

-setting : multicenter, recruitment : at a university center, general practices, pharmacies and company
employees
-inclusion criteria: common cold with runny nose rated moderate or severe (primary complaint) and at
least one additional symptom : stuffy nose, sneezing/itchy nose, headache/fullness in head, watery eyes/
itchy eyes.
-exclusion : exudative pharyngitis, body temperature >38c, patients feeling seriously ill, known history of
allergic rhinitis, asthma, or atopic eczema, use of common cold medication (combination of AH, decon-
gestants, analgesics), corticosteroids, antibiotics during past week; known hypersensitivity to terfenadine,
other serious disease or underlying conditions , pregnancy or possibility of becoming pregnant during the
study.
Duration of symptoms before inclusion : 6 to 48h
Interventions terfenadine 60 mg 2/d

duration of treatment : 1 1/2 day
Outcomes 2 hours and 12 hours after 1st drug intake and 2 to 5 hours after 2nd intake:
1.severity scores of runny nose/stuffy nose/sneezing*
2.overall efficacy

Henauer 1988 (Continued)
3.tolerability : open questions for side effects

4.rhinomanometry : mean nasal air flow
5.rhinoscopia: severity score of obstruction, secretion, swelling, redness
Notes 28 patients who violated the protocol were identified before breaking the treatment code. They were
analyzed separately. Data on these patients were not used in this review. Rhinomanometry and rhinoscopia
are performed on only 16 of the eligible patient. It is not clear how they were selected
Risk of bias
Howard 1979
Methods a. SF10, J2-2-0

b. RCT double blind placebo controlled trial
c.natural colds
d.271 patients evaluated
e. % follow up not clear
Participants -age : adults

-setting : multicoated, recruitment : unclear - patients were kept under observation
-inclusion : 1. symptom score of at least 6
(scoring system : sore throat (0 to 4), nasal discharge and congestion, sneezing, PND, cough (0 to 3))
+ 2. signs score (physical examination) of at least 5 (nasal swelling, nasal redness, nasal secretion, obstruction
right nostril, obstruction left nostril (0 to 3)
-exclusion : > 37.8 c, severe sore throat, exudative pharyngitis, history of allergic rhinitis or asthma
or atopic eczema, concomitant pulmonary or pharyngeal infection, occupation for which AH might be
hazardous, use of other medications : aspirin or other analgesics, antihistamines, decongestants, steroids,
antibiotics, medications for chronic conditions that did involve the upper respiratory tract.
-duration of symptoms before inclusion : < 48 h
Interventions chlorpheniramine maleate 4x / d

Outcomes 1.overall physician evaluation after 2 days of treatment

2. overall patient evaluation after 1 and 6 days of treatment
3.score for nasal discharge, sneezing, nose blowing* at different times
4. side effects
Notes
Risk of bias

Howard 1979 (Continued)
Hugenin 1988
Methods a. SF 9 J 0.2.1
b. RCT double blind placebo controlled trial
c. natural colds
e. 81% follow up
Participants -age : 2-15

-setting : pediatric consultation (?); recruitment : no clear
-inclusion : watery or mucous rhinorrhea, cough, malaise
-exclusion : history of allergy, signs of bronchitis, signs of bacterial surinfection : positive strep A on throat
swab, > 10 000 leucytes/mm, fever.
-duration of symptoms before inclusion : average of 6 - 7 days
Interventions astemizole 0.2 mg/kg 1x/day

Outcomes 1. mean daily score and % decrease in severity score of rhinorrhoea from base line
2. time until severity score of rhinorrhea, cough and general condition has decreased with 50 %
3. proportion of patients cured after 3 days and 7 days
Notes no mentioning of randomisation

mean duration of symptoms before inclusion is 6 days (range 1-365 days)
Risk of bias
Hutton 1991
c. natural colds
d. 54 children included
e. 87% follow-up
Participants -age : children 6mnth-5yrs.

-setting : pediatric walk in clinic and pediatric primary care clinic.
-inclusion criteria : symptoms of cold, and signs of URTI (i.e. nasal congestion or rhinorrhoea)
-exclusion : signs or symptoms of a more serious or treatable disease (t> 38.9, vomiting, > 3 loose
stools in 24 hours, stridor, wheezing, chest retractions, laboratory tests ordered, antibiotics prescribed) ;
contraindications to medication (e.g. history of seizures or other neurologic problem)

Hutton 1991 (Continued)
Study carried out in winter period to avoid allergic episodes

duration of symptoms before enrolment not mentioned
Interventions brompheniramine maleate 4mg/5ml+ phenylephrine hydrochloride 4mg/5ml+ phenylpropanolamine hy-

drochloride 5mg/5ml. Dose : 0.5 0.75 mg/kg brompheniramine /day in 3 gifts.
duration of treatment : 2 days.
Outcomes 1.symptom severity score change (congested of runny nose*)

2.number of children (as reported by parents) with overall improvement after 2 days
3.number of children (as reported by parents) with improvement of congested or runny nose
Notes duration of symptoms before inclusion not mentioned
Risk of bias
Lebacq 1994
b. RCT single blind placebo controlled trial (3 arms)
c. natural cold
d. 36 patients tested
e.100% follow-up
Participants -age : adults (25-39 yr) and children (6-12yr)

-setting : hospital, recruitment : unclear ; patients under standardised circumstances and closely followed-
up during one day
-inclusion :impaired nasal respiration due to acute congestive rhinitis
-exclusion : any concurrent disease other than acute congestive rhinitis, insufficiency of any etiology, any
drug treatment undertaken within 15 days before the study; participation to another clinical trial within
the previous 3 months
-duration of symptoms before treatment : not mentioned
Interventions 1.rhinopront (300 mg phenylpropanolamine + 24 mg carbinoxamine / 100gr syrup)

adults : 15 gr
children : 1 gr / yr
2.traminic (tablets : 50 mg phenylpropanolamine hcl, 25 mg pheniramine maleate, 25 mg mepyramine
maleate, 80 mg colffeine monohydraat; drops : 10 mg phynylpropanolamine hydrochloride, 10 mg
pheniamine maleaat, 10 mg mepyramine maleat / ml)
-duration : adults : one single dose; children : 4 days
Outcomes 1. nasal resistance at several moments after administration of 1 single dose

2. clinical score at several moments after administration of 1 dose ( nasal congestion, aspect of nasal
mucosa)
3. children : daily nasal congestion severity score during 4 days of treatment

Lebacq 1994 (Continued)
4. side-effects
Notes participants blinded?

duration of symptoms before inclusion not mentioned
possible inclusion of allergic patients
Risk of bias
Lorriman 1950
c. natural colds
d.81% after 1 day, 71% after 2 days, 45% after 7 days
e.1744 patients included
Participants -age : not specified

-setting : 8 factories, 1 school, recruitment : not clear
-inclusion : cold (symptoms not defined)
-exclusion :not specified
-duration of symptoms : <24 h
Interventions antistin 0.1 gr 1X/4h (except night)

duration of treatment : 2 days (9 tablets)
Outcomes proportion of patients improved or cured after 1 day of treatment, after 2 days of treatment , after 7 days
of treatment
Notes allocation by rotation (4 codes used instead of 2)
Risk of bias
Allocation concealment? No C - Inadequate

MRC (Part II) 1950
Methods a. SF 10 J 2-2-0.
c. natural colds
e. 75% follow-up
Participants -age : > 15 yr

-setting : several research centres - recruitment : participants recruited by advertisement.
-inclusion : catarrhal inflammation upper respiratory passages, usually without pyrexia, but with watery or
mucous discharge from the nose and associated with sneezing, fullness in the head and nose,and sometimes
with cough, headache, sore throat, hoarseness and running eyes
-exclusion : chronic catarrh or sinusitis, acute tonsillitis, suspected influenza, t > 37.8, AH in previous
week , present attack of hay fever of allergic rhinitis,( previous history of allergic states were included -
but registered)
-duration of symptoms before inclusion : 80% of patients <48 h
Interventions thonzylamine 50mg3co/d

duration of treatment : 3d
Outcomes 1. proportion of patients cured or improved after 1 day of treatment, after 2 days of treatment, after 1
week of treatment
2.side-effects
Notes
Risk of bias
Muether 2001
d. 53 patients experimentally infected
e. 100% follow up of infected patients
Participants -age : 18 to 40 yr
-setting : university, recruitment : unclear; patients kept under observation
-inclusion : healthy volunteers with proven experimental infection with rhinovirus type 16
-exclusion : antibody titer against rhinovirus type 16 >2, free of colds or fever >37.8 during last week,
history of hypersensitivity to antihistamines, history of allergic rhinitis, bronchial asthma, lower respiratory
tract infections (COPD, emphysema), alcohol or drug abuse, use of investigational drug within 30d,
AH or cold preparations within 14 d, MAO-inhibitors within 1 week, astemizole within 90 d, other
medication that might interfere with study, pregnancy, lactation, glaucoma, renal, hepatic, endocrine,
digestive, genito-urinary, neurologic and psychologic diseases.
duration of symptoms before inclusion : treatment is started before infection

Muether 2001 (Continued)
Interventions -loratadine 10 mg / d
duration of treatment : start 7 days before virus inoculation until 5 days after (inoculation on day 8)
Outcomes 1. daily evaluation of symptoms severity scores (sneezing, runny nose, nasal obstruction*) during 5 days
after virus challenge
2. daily measurement of nasal secretion weight
3. count of daily sneezes
Notes of infected volunteers, only 70% met criteria for illness - it is not clear whether others had also symptoms
or not
Risk of bias
Sakchainanont 1990
c. natural colds
d.150 children included
e.95% follow-up
Participants -age : under 5 years

-setting : pediatric out patient department, recruitment : patients presenting to the clinic
-inclusion : rhinorrhea of 3 days duration
-exclusion : fever >38, use of other medication received, history of allergy, nasal eosinophil count > 10%,
other bacterial infection
-duration of symptoms before inclusion : 3 days
Interventions clemastine fumarate 0.05 mg/kg/d 2x/d

chlorpheniramine maleate syrup 0.35 mg/ kg /d 3x/d
duration of treatment before evaluation : 3 days
Outcomes evaluation after 3 days of treatment of amount

1. of nasal discharge
2. of aspects of nasal turbinates (amount of edema),
3. of drowsiness/sleepiness (et al)
Notes duration of symptoms before inclusion is more than 48 hours
Risk of bias

Sakchainanont 1990 (Continued)
Scavino 1985
c. natural colds
e. 83% follow-up
Participants -age : 6 or older

-setting : university, recruitment : unclear,
-inclusion : sum of scores on rhinorrhoea, nasal congestion, cough, sneezing, post nasal drip, lacrimation
(scale 0 to 3) is minimal 8; rhinorrhoea or nasal obstruction and cough score minimal 2, or rhinorrhea,
cough and nasal obstruction all at least 1.
-exclusion : < 12 yr, pregnancy, lactation, hypersensitivity to study medication. Renal, hepatic or serious
cardiovascular disease. Hypertension, arrhythmias, hyperthyroidism, peptic ulcers, pyloroduodenal ob-
struction, glaucoma, predisposition to urinary retention, prostatic hypertrophy, asthma, allergic respira-
tory disease or other serious illnesses. Concomitant pulmonary, nasopharyngeal or sinus bacterial infec-
tion, severe sore throat, exudative pharyngitis, temperature > 37.8 c. Therapy with oral corticosteroids
within 5 days, parental corticosteroids within 3 weeks (depot 6 w), intranasal corticoids within 2 weeks,
treatment with MAO-inhibitors, other medication that might affect action of study agents
duration of symptoms before inclusion : max 48 h
Interventions -azatadine maleate 1 mg, pseudoephedrine sulfate 60 mg, dextromethorphan hydrobromide 20 mg / 5 cc

3x/day
-duration of therapy : 5days
Outcomes Evaluation on day 3 and 5 of treatment of:

1. global evaluation by physician
2. side effects
Notes
Risk of bias

Tebrock 1973
Methods a. SF 10 J1-1-1
c. natural colds
e. 85% follow-up
Participants -age: 18 or older

-setting: multicenter, recruitment : employees of General Telephone and Electronics,
-inclusion : healthy, having cough and common cold (afebrile acute coryza of viral origin or undifferentiated
upper respiratory tract infection)
-exclusion: hypersensivity to diphenhydramine, acute asthmatic attack, narrow-angle glaucoma, prostatic
hypertrophy, stenosing peptic ulcer, pyloroduodenal obstruction, bladder neck obstruction, therapy with
MAO inhibitors
-duration of symptoms before inclusion : not mentioned
Interventions - benadryl HCL 25 mg 4X/d

- duration of therapy : 3 days
Outcomes 1.improvement of nasal obstruction at day 1, 2 and 3

2.global evaluation by investigator
3.side effects
Notes - allergic rhinitis not explicitly excluded

- duration of symptoms before inclusion unknown
- investigators blinded?
- results on nasal obstruction:only for patients with nasal obstruction at entry
Risk of bias
Thackray 1978
b. RCT double blind placebo controlled cross over
c. natural colds
e. 100% follow-up
Participants - 18 to 60
-setting: doctors surgeries (general practice?) - patients seeking help for their cold
-inclusion: common cold
-exclusion: not mentioned
-duration of symptoms before inclusion : not mentioned

Thackray 1978 (Continued)
Interventions active syrup containing :

-dextromethorphan 15 mg + ephedrine 8mg + doxylamine 7.5 mg + paracetamol 600 mg per 30 ml
one single dose of 30 ml before bed, evaluation on next morning
Outcomes rating on 6-point scale of efficacy of medication on : nasal congestion, nasal discharge, sneezing and
generally feeling unwell during the night *:
comparison of number of positive rating after one dose of active syrup of placebo syrup
Notes
Risk of bias
Turner 1997
c. natural colds
e. 94.3% follow-up
Participants -age: >18 or older (1000 healthy subjects under observation and included when getting a cold)
-setting : university ; recruitment : by advertisements
-inclusion in study : participant under observation gets common cold symptom ( i.e. : headache, muscle
ache, runny nose, sneezing,stopped-up nose,sore throat, scratchy throat, cough, hoarseness, postnasal drip,
feverishness, chilliness, and feeling sick.; at least two different symptoms must be present for less than 24
h and one symptoms is sneezing or rhinorrhea). Participants answer yes when asked: have you had the
onset of a cold within the last 24 hours?
-exclusion : medication use which can interfere with antihistamines or which may make evaluation of
common cold symptoms difficult; underlying illnesses that might be exacerbated by antihistamines or that
might affect the assessment of common cold symptoms, present allergies (history of seasonal or perennial
allergic rhinitis is not an exclusion criterion, present complaints is), pregnancy.
-duration of symptoms before inclusion : 24 h
Interventions -clemastine fumarate 1.34 mg or placebo 2 x pd

-duration of treatment : 5 days
Outcomes 1. rhinorrhoea and sneezing severity scores on day 2 and 3

2.side effects
Notes
Risk of bias

Turner 1997 (Continued)
Virtanen 1983
Methods a. SF10 J1-2-1

c. natural colds
e.87% foolow-up
Participants -age: adults, volunteers

-setting: university hospital, recruitment : from university population
-inclusion: acute rhinitis with common cold
-exclusion: fever, allergic manifestations, sinusitis or other diseases, use of other cold preparations, steroids,
antibiotics during study
-duration of cold before enrolment : max 48 h
Interventions -slow release dexchlorpheniramine maleate 6 mg, pseudoefedrine 120 mg) 2 x / d

-duration of treatment : 5 days
Outcomes 1. daily score of nose obstruction, secretion, sneezing *

2. side effects
Notes
Risk of bias
* : in this study more effect on more symptoms was evaluated. The table only mentions outcomes used in the review.
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Jaff 1983 no placebo group
Jansen 1983 mixed population of patients with common cold and allergy

(Continued)
Kaminszczik 1983 mixed population of patients with common cold and allergy
Lea 1984 decongestant is phenylpropanolamine, not an antihistamine
Maranta 1996 no placebo control
Mc Laurin 1966 effect on nasal obstruction

etiology of nasal obstruction is not clear
common cold not mentioned
McCormick 1996 patients have radiologically confirmed sinusitis, not common cold
individual symptoms are not discussed, only total scores (outcome measures as described in the protocol are
not extractable)
all patients were treated with antibiotics
McGuiness 1976 no placebo control
Meurman 1975 no placebo control
Middleton 1981 no placebo group
MRC (Part 1) 1950 study on the prevention of common cold by AH after experimental virus instillation
Riu 1976 part 1 : no control group

part 2 : allergic patients not excluded (15 of 30 patients had allergic rhinitis)
US NAVY 1950 part 1 : prevention of common cold by AH

part 2 : therapeutic trial but time of evaluation is not mentioned: comparison of number of recruits recovered
at survey, but date of survey unknown - outcome vaguely described
part 3 : follows recruits with pretreatment symptoms of cold : in final results are head and chest cold together
(42% were chest colds : namely primarily symptoms of lower respiratory tract - not common cold)
Weippl 1984 no placebo group

DATA AND ANALYSES
Comparison 1. Monotherapy - global evaluation - all trials
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Short term (1-2 days) 5 3492 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.97 [0.85, 1.12]
2 Intermediate term (3-4 days) 3 1301 Odds Ratio (M-H, Fixed, 95% CI) 1.08 [0.83, 1.41]
3 Long term (6-10 days) 4 2296 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.93 [0.77, 1.12]
4 Trials with acceptable quality - 3 1490 Odds Ratio (M-H, Fixed, 95% CI) 0.74 [0.60, 0.92]
short term (1-2 days)
intermediate term (3-4 days)
6 Trials with acceptable quiality - 3 1551 Odds Ratio (M-H, Fixed, 95% CI) 0.88 [0.70, 1.10]
long term (6-10 days)
Comparison 2. Monotherapy - global evaluation - trials with 1st generation antihistamines
No. of No. of
1 All trials - short term (1-2 days) 4 3429 Odds Ratio (M-H, Fixed, 95% CI) 0.93 [0.79, 1.09]
2 All trials - intermediate term 2 1067 Odds Ratio (M-H, Fixed, 95% CI) 1.05 [0.78, 1.42]
(3-4 days)
3 All trials -long term (6-10 days) 4 2296 Odds Ratio (M-H, Fixed, 95% CI) 0.90 [0.74, 1.08]
short term (1 -2 days)
intermediate term (3-4 days)
long term (6-10 days)
Comparison 3. Monotherapy - subjective severity assessment of nasal obstruction - all trials
No. of No. of
1 Mean severity score after 1 day 3 428 Mean Difference (IV, Fixed, 95% CI) -0.09 [-0.23, 0.05]
of treatment
2 Mean severity score after 3-5 5 758 Mean Difference (IV, Fixed, 95% CI) 0.05 [-0.08, 0.17]
days of treatment

Comparison 4. Monotherapy - subjective severity assessment of nasal obstruction - non-sedating antihistamines
No. of No. of
of treament
2 Mean severity score after 3-5 3 383 Mean Difference (IV, Fixed, 95% CI) 0.22 [0.03, 0.40]
days of treatment
Comparison 5. Monotherapy - subjective severity assessment of nasal obstruction - 1st generation antihistamines
No. of No. of
of treatment
2 Mean severity score after 3-5 2 375 Mean Difference (IV, Fixed, 95% CI) -0.11 [-0.28, 0.07]
days of treatment
Comparison 6. Monotherapy - weight of expelled nasal mucus
No. of No. of
1 3rd day after virus challenge 5 479 Mean Difference (IV, Fixed, 95% CI) -1.61 [-2.99, -0.24]
2 4th day after virus challenge 5 479 Mean Difference (IV, Fixed, 95% CI) -1.41 [-2.44, -0.39]
3 5th day after virus challenge 4 456 Mean Difference (IV, Fixed, 95% CI) -0.46 [-1.14, 0.23]
4 Total weight of nasal mucus over 4 124 Mean Difference (IV, Fixed, 95% CI) -0.14 [-5.37, 5.09]
4-5 days after virus challenge
Comparison 7. Monotherapy - subjective severity assessment of rhinorrhoea - all trials
No. of No. of
1 First treatment day 6 1753 Mean Difference (IV, Fixed, 95% CI) -0.05 [-0.12, 0.02]
2 Second treatment day 6 1752 Mean Difference (IV, Fixed, 95% CI) -0.15 [-0.23, -0.07]
3 Third treatment day 6 1744 Mean Difference (IV, Fixed, 95% CI) -0.13 [-0.22, -0.05]
4 Fourth treatment day 6 1145 Mean Difference (IV, Fixed, 95% CI) -0.18 [-0.27, -0.10]

Comparison 8. Monotherapy - subjective severity assessment of rhinorrhoea - non sedating antihistamines
No. of No. of
1 Fourth treatment day 3 383 Mean Difference (IV, Fixed, 95% CI) -0.08 [-0.23, 0.08]
Comparison 9. Monotherapy - subjective severity assessment of rhinorrhoea - 1st generation antihistamines
No. of No. of
1 First treatment day 4 1466 Mean Difference (IV, Fixed, 95% CI) -0.04 [-0.12, 0.04]
Comparison 10. Monotherapy - sneeze counts
No. of No. of
1 Day 2 after virus challenge 2 375 Mean Difference (IV, Fixed, 95% CI) -2.28 [-3.42, -1.14]
Comparison 11. Monotherapy - subjective severity assesment of sneezing - all trials
No. of No. of
1 First treatment day 4 1466 Mean Difference (IV, Fixed, 95% CI) -0.07 [-0.14, -0.00]

Comparison 12. Monotherapy - subjective severity assessment of sneezing - 1st generation antihistamines
No. of No. of
1 First treatment day 4 1466 Mean Difference (IV, Fixed, 95% CI) -0.07 [-0.14, -0.00]
Comparison 13. Monotherapy - side effects
No. of No. of
1 Side effects : all - all trials 11 3245 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.25 [1.04, 1.50]
2 Side effects : all - non-sedating 3 215 Odds Ratio (M-H, Fixed, 95% CI) 1.12 [0.50, 2.51]
antihistamines
3 Side effects : first generation 8 3030 Odds Ratio (M-H, Fixed, 95% CI) 1.25 [1.04, 1.52]
antihistamines
4 Side effects : sedation - all trials 8 3389 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.74 [1.32, 2.29]
5 Side effects : sedation - 2 349 Odds Ratio (M-H, Fixed, 95% CI) 1.06 [0.50, 2.26]
non-sedating antihistamines
6 Side effects : sedation - first 6 3040 Odds Ratio (M-H, Fixed, 95% CI) 1.90 [1.39, 2.59]
generation antihistamines
7 Side effects : gastro-intestinal 7 2351 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.57 [0.97, 2.55]
8 Side effects : sleeplessness 3 1625 Peto Odds Ratio (Peto, Fixed, 95% CI) 3.12 [0.94, 10.36]
9 Side effect : dry nose 2 173 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.90 [0.97, 3.73]
10 Side effects : headache 5 2104 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.19 [0.76, 1.85]
11 Side effects: vertigo, dizziness 4 1502 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.34 [0.72, 2.50]
12 Side effects : dry mouth 3 421 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.14 [0.60, 2.17]
Comparison 14. Combination therapy - global evaluation
No. of No. of
1 Combination therapy - global 2 94 Odds Ratio (M-H, Fixed, 95% CI) 0.18 [0.06, 0.49]
evaluation after 2 to 4 days of
treatment
2 Combination therapy - global 3 213 Odds Ratio (M-H, Fixed, 95% CI) 0.21 [0.11, 0.42]
evalution at final evaluation
time

Comparison 15. Combination therapy - side effects
No. of No. of
1 Side-effects : all 6 591 Odds Ratio (M-H, Fixed, 95% CI) 1.33 [0.90, 1.96]
2 Side-effects : drowsiness, 4 478 Odds Ratio (M-H, Fixed, 95% CI) 1.00 [0.58, 1.72]
hypersomia and excessive
sleepiness
3 Side-effects : dry mouth 3 426 Odds Ratio (M-H, Fixed, 95% CI) 4.02 [1.89, 8.51]
4 Side-effects : insomnia 2 334 Odds Ratio (M-H, Fixed, 95% CI) 1.27 [0.61, 2.64]
5 Side-effects : gastro-intestinal 2 165 Odds Ratio (M-H, Fixed, 95% CI) 0.57 [0.18, 1.78]
Analysis 1.1. Comparison 1 Monotherapy - global evaluation - all trials, Outcome 1 Short term (1-2 days).
Review: Antihistamines for the common cold
Comparison: 1 Monotherapy - global evaluation - all trials
Outcome: 1 Short term (1-2 days)
Peto Peto
Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio
n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI
Cowan 1950 283/388 139/207 13.9 % 1.32 [ 0.91, 1.92 ]
Henauer 1988 11/28 21/35 2.0 % 0.44 [ 0.17, 1.19 ]
Howard 1979 97/133 112/138 6.0 % 0.63 [ 0.36, 1.11 ]
Lorriman 1950 306/697 286/710 42.6 % 1.16 [ 0.94, 1.43 ]
MRC (Part II) 1950 301/579 334/577 35.6 % 0.79 [ 0.63, 0.99 ]
Total (95% CI) 1825 1667 100.0 % 0.97 [ 0.85, 1.12 ]

Total events: 998 (Treatment), 892 (Control)
Heterogeneity: Chi2 = 13.22, df = 4 (P = 0.01); I2 =70%
Test for overall effect: Z = 0.37 (P = 0.71)
Test for subgroup differences: Not applicable
0.1 0.2 0.5 1 2 5 10

Favours treatment Favours control

Analysis 1.2. Comparison 1 Monotherapy - global evaluation - all trials, Outcome 2 Intermediate term (3-4
days).
Outcome: 2 Intermediate term (3-4 days)

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Cowan 1950 215/388 110/207 61.6 % 1.10 [ 0.78, 1.54 ]
Gaffey 1988 88/119 81/115 20.7 % 1.19 [ 0.67, 2.11 ]
Tebrock 1973 18/236 20/236 17.8 % 0.89 [ 0.46, 1.73 ]
Total (95% CI) 743 558 100.0 % 1.08 [ 0.83, 1.41 ]

Heterogeneity: Chi2 = 0.44, df = 2 (P = 0.80); I2 =0.0%
0.1 0.2 0.5 1 2 5 10


Analysis 1.3. Comparison 1 Monotherapy - global evaluation - all trials, Outcome 3 Long term (6-10 days).
Outcome: 3 Long term (6-10 days)
Peto Peto
Bye 1980 34/61 49/63 6.5 % 0.37 [ 0.18, 0.78 ]
Howard 1979 38/133 50/138 14.0 % 0.71 [ 0.42, 1.17 ]
Lorriman 1950 90/379 83/366 31.2 % 1.06 [ 0.76, 1.49 ]
MRC (Part II) 1950 137/579 132/577 48.4 % 1.04 [ 0.80, 1.37 ]
Total (95% CI) 1152 1144 100.0 % 0.93 [ 0.77, 1.12 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.4. Comparison 1 Monotherapy - global evaluation - all trials, Outcome 4 Trials with acceptable
quality - short term (1-2 days).
Outcome: 4 Trials with acceptable quality - short term (1-2 days)

Henauer 1988 11/28 21/35 5.6 % 0.43 [ 0.16, 1.19 ]
Howard 1979 97/133 112/138 14.8 % 0.63 [ 0.35, 1.11 ]
MRC (Part II) 1950 301/579 334/577 79.6 % 0.79 [ 0.62, 0.99 ]
Total (95% CI) 740 750 100.0 % 0.74 [ 0.60, 0.92 ]

0.1 0.2 0.5 1 2 5 10

quality - intermediate term (3-4 days).
Outcome: 5 Trials with acceptable quality - intermediate term (3-4 days)

Gaffey 1988 88/119 81/115 53.7 % 1.19 [ 0.67, 2.11 ]
Tebrock 1973 18/236 20/236 46.3 % 0.89 [ 0.46, 1.73 ]
Total (95% CI) 355 351 100.0 % 1.05 [ 0.68, 1.62 ]

0.1 0.2 0.5 1 2 5 10


quiality - long term (6-10 days).
Outcome: 6 Trials with acceptable quiality - long term (6-10 days)

Bye 1980 34/61 49/63 13.6 % 0.36 [ 0.16, 0.78 ]
Howard 1979 38/133 50/138 22.3 % 0.70 [ 0.42, 1.17 ]
MRC (Part II) 1950 137/579 132/577 64.2 % 1.04 [ 0.80, 1.37 ]
Total (95% CI) 773 778 100.0 % 0.88 [ 0.70, 1.10 ]

0.1 0.2 0.5 1 2 5 10


Analysis 2.1. Comparison 2 Monotherapy - global evaluation - trials with 1st generation antihistamines,
Outcome 1 All trials - short term (1-2 days).
Comparison: 2 Monotherapy - global evaluation - trials with 1st generation antihistamines
Outcome: 1 All trials - short term (1-2 days)

Cowan 1950 283/388 139/207 15.8 % 1.32 [ 0.91, 1.90 ]
Howard 1979 97/133 112/138 9.6 % 0.63 [ 0.35, 1.11 ]
Lorriman 1950 90/697 83/710 23.0 % 1.12 [ 0.81, 1.54 ]
MRC (Part II) 1950 301/579 334/577 51.6 % 0.79 [ 0.62, 0.99 ]
Total (95% CI) 1797 1632 100.0 % 0.93 [ 0.79, 1.09 ]

0.1 0.2 0.5 1 2 5 10

Outcome 2 All trials - intermediate term (3-4 days).
Outcome: 2 All trials - intermediate term (3-4 days)

Cowan 1950 215/388 110/207 77.6 % 1.10 [ 0.78, 1.54 ]
Tebrock 1973 18/236 20/236 22.4 % 0.89 [ 0.46, 1.73 ]
Total (95% CI) 624 443 100.0 % 1.05 [ 0.78, 1.42 ]

0.1 0.2 0.5 1 2 5 10


Outcome 3 All trials -long term (6-10 days).
Outcome: 3 All trials -long term (6-10 days)

Bye 1980 34/61 49/63 9.5 % 0.36 [ 0.16, 0.78 ]
Howard 1979 38/133 50/138 15.5 % 0.70 [ 0.42, 1.17 ]
Lorriman 1950 289/379 283/366 30.3 % 0.94 [ 0.67, 1.32 ]
MRC (Part II) 1950 137/579 132/577 44.7 % 1.04 [ 0.80, 1.37 ]
Total (95% CI) 1152 1144 100.0 % 0.90 [ 0.74, 1.08 ]

0.1 0.2 0.5 1 2 5 10


Outcome 4 Trials with acceptable quality - short term (1 -2 days).
Outcome: 4 Trials with acceptable quality - short term (1 -2 days)

Howard 1979 97/133 112/138 15.6 % 0.63 [ 0.35, 1.11 ]
MRC (Part II) 1950 301/579 334/577 84.4 % 0.79 [ 0.62, 0.99 ]
Total (95% CI) 712 715 100.0 % 0.76 [ 0.61, 0.95 ]

0.1 0.2 0.5 1 2 5 10

Outcome 5 Trials with acceptable quality - intermediate term (3-4 days).
Outcome: 5 Trials with acceptable quality - intermediate term (3-4 days)

Tebrock 1973 18/236 20/236 100.0 % 0.89 [ 0.46, 1.73 ]
Total (95% CI) 236 236 100.0 % 0.89 [ 0.46, 1.73 ]

Heterogeneity: not applicable
0.1 0.2 0.5 1 2 5 10


Outcome 6 Trials with acceptable quality - long term (6-10 days).
Outcome: 6 Trials with acceptable quality - long term (6-10 days)

Bye 1980 34/61 49/63 13.6 % 0.36 [ 0.16, 0.78 ]
Howard 1979 38/133 50/138 22.3 % 0.70 [ 0.42, 1.17 ]
MRC (Part II) 1950 137/579 132/577 64.2 % 1.04 [ 0.80, 1.37 ]
Total (95% CI) 773 778 100.0 % 0.88 [ 0.70, 1.10 ]

0.1 0.2 0.5 1 2 5 10


Analysis 3.1. Comparison 3 Monotherapy - subjective severity assessment of nasal obstruction - all trials,
Outcome 1 Mean severity score after 1 day of treatment.
Comparison: 3 Monotherapy - subjective severity assessment of nasal obstruction - all trials
Outcome: 1 Mean severity score after 1 day of treatment
Mean Mean
Study or subgroup Treatment Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Gwaltney 1996 75 0.83 (0.76) 75 0.77 (0.76) 31.1 % 0.06 [ -0.18, 0.30 ]
Gwaltney 1997 113 0.42 (0.64) 112 0.59 (0.74) 56.2 % -0.17 [ -0.35, 0.01 ]
Muether 2001 29 0.28 (0.6) 24 0.38 (0.78) 12.7 % -0.10 [ -0.48, 0.28 ]
Total (95% CI) 217 211 100.0 % -0.09 [ -0.23, 0.05 ]

-10 -5 0 5 10

Analysis 3.2. Comparison 3 Monotherapy - subjective severity assessment of nasal obstruction - all trials,
Outcome 2 Mean severity score after 3-5 days of treatment.
Comparison: 3 Monotherapy - subjective severity assessment of nasal obstruction - all trials
Outcome: 2 Mean severity score after 3-5 days of treatment
Mean Mean
Berkowitz 1991 48 1.21 (1.04) 48 1.25 (0.97) 9.9 % -0.04 [ -0.44, 0.36 ]
Gaffey 1988 119 1.3 (0.8) 115 1 (0.9) 33.7 % 0.30 [ 0.08, 0.52 ]
Gwaltney 1996 75 1.2 (0.76) 75 1.13 (0.87) 23.5 % 0.07 [ -0.19, 0.33 ]
Gwaltney 1997 113 1.04 (0.85) 112 1.29 (0.95) 28.9 % -0.25 [ -0.49, -0.01 ]
Muether 2001 29 1.52 (1.02) 24 1.38 (1.3) 3.9 % 0.14 [ -0.50, 0.78 ]
Total (95% CI) 384 374 100.0 % 0.05 [ -0.08, 0.17 ]

-10 -5 0 5 10

Analysis 4.1. Comparison 4 Monotherapy - subjective severity assessment of nasal obstruction - non-
sedating antihistamines, Outcome 1 Mean severity score after 1 day of treament.
Comparison: 4 Monotherapy - subjective severity assessment of nasal obstruction - non-sedating antihistamines
Outcome: 1 Mean severity score after 1 day of treament
Mean Mean
Muether 2001 29 0.28 (0.6) 24 0.38 (0.78) 100.0 % -0.10 [ -0.48, 0.28 ]
Total (95% CI) 29 24 100.0 % -0.10 [ -0.48, 0.28 ]

Heterogeneity: not applicable
-10 -5 0 5 10
Analysis 4.2. Comparison 4 Monotherapy - subjective severity assessment of nasal obstruction - non-
sedating antihistamines, Outcome 2 Mean severity score after 3-5 days of treatment.
Comparison: 4 Monotherapy - subjective severity assessment of nasal obstruction - non-sedating antihistamines
Mean Mean
Berkowitz 1991 48 1.21 (1.04) 48 1.25 (0.97) 20.9 % -0.04 [ -0.44, 0.36 ]
Gaffey 1988 119 1.3 (0.8) 115 1 (0.9) 70.8 % 0.30 [ 0.08, 0.52 ]
Muether 2001 29 1.52 (1.02) 24 1.38 (1.3) 8.3 % 0.14 [ -0.50, 0.78 ]
Total (95% CI) 196 187 100.0 % 0.22 [ 0.03, 0.40 ]

-10 -5 0 5 10

Analysis 5.1. Comparison 5 Monotherapy - subjective severity assessment of nasal obstruction - 1st
generation antihistamines, Outcome 1 Mean severity score after 1 day of treatment.
Comparison: 5 Monotherapy - subjective severity assessment of nasal obstruction - 1st generation antihistamines
Outcome: 1 Mean severity score after 1 day of treatment
Mean Mean
Gwaltney 1996 75 0.83 (0.76) 75 0.77 (0.76) 35.6 % 0.06 [ -0.18, 0.30 ]
Gwaltney 1997 113 0.42 (0.64) 112 0.59 (0.74) 64.4 % -0.17 [ -0.35, 0.01 ]
Total (95% CI) 188 187 100.0 % -0.09 [ -0.23, 0.06 ]

-10 -5 0 5 10

Analysis 5.2. Comparison 5 Monotherapy - subjective severity assessment of nasal obstruction - 1st
generation antihistamines, Outcome 2 Mean severity score after 3-5 days of treatment.
Comparison: 5 Monotherapy - subjective severity assessment of nasal obstruction - 1st generation antihistamines
Mean Mean
Gwaltney 1996 75 1.2 (0.76) 75 1.13 (0.87) 44.8 % 0.07 [ -0.19, 0.33 ]
Gwaltney 1997 113 1.04 (0.85) 112 1.29 (0.95) 55.2 % -0.25 [ -0.49, -0.01 ]
Total (95% CI) 188 187 100.0 % -0.11 [ -0.28, 0.07 ]

-10 -5 0 5 10

Analysis 6.1. Comparison 6 Monotherapy - weight of expelled nasal mucus, Outcome 1 3rd day after virus
challenge.
Comparison: 6 Monotherapy - weight of expelled nasal mucus
Outcome: 1 3rd day after virus challenge
Mean Mean
Gaffey 1987a 12 7.1 (5.7) 11 9.4 (16.1) 1.9 % -2.30 [ -12.35, 7.75 ]
Gaffey 1987b 13 2.6 (3.8) 15 2.4 (3.3) 26.9 % 0.20 [ -2.46, 2.86 ]
Gwaltney 1996 75 3.62 (5.2) 75 6.32 (13.86) 16.9 % -2.70 [ -6.05, 0.65 ]
Gwaltney 1997 113 4.75 (6.17) 112 7.68 (9.1) 45.9 % -2.93 [ -4.96, -0.90 ]
Muether 2001 29 6.71 (7.5) 24 4.61 (9.68) 8.5 % 2.10 [ -2.64, 6.84 ]
Total (95% CI) 242 237 100.0 % -1.61 [ -2.99, -0.24 ]

-10 -5 0 5 10

Analysis 6.2. Comparison 6 Monotherapy - weight of expelled nasal mucus, Outcome 2 4th day after virus
challenge.
Outcome: 2 4th day after virus challenge
Mean Mean
Gaffey 1987a 12 5.6 (6.7) 11 5.7 (5.9) 4.0 % -0.10 [ -5.25, 5.05 ]
Gaffey 1987b 13 3.1 (6) 15 3 (4.2) 7.0 % 0.10 [ -3.79, 3.99 ]
Gwaltney 1996 75 3.27 (4.42) 75 4.54 (7.36) 28.0 % -1.27 [ -3.21, 0.67 ]
Gwaltney 1997 113 3.3 (4.04) 112 5.27 (6.14) 57.2 % -1.97 [ -3.33, -0.61 ]
Muether 2001 29 8.93 (6.52) 24 7.21 (11.74) 3.8 % 1.72 [ -3.54, 6.98 ]
Total (95% CI) 242 237 100.0 % -1.41 [ -2.44, -0.39 ]

-10 -5 0 5 10

Analysis 6.3. Comparison 6 Monotherapy - weight of expelled nasal mucus, Outcome 3 5th day after virus
challenge.
Outcome: 3 5th day after virus challenge
Mean Mean
Gaffey 1987b 13 1.6 (2.7) 15 1.4 (1.8) 15.8 % 0.20 [ -1.53, 1.93 ]
Gwaltney 1996 75 1.81 (2.51) 75 2.59 (5.12) 28.2 % -0.78 [ -2.07, 0.51 ]
Gwaltney 1997 113 2.05 (3.83) 112 2.61 (3.39) 52.7 % -0.56 [ -1.50, 0.38 ]
Muether 2001 29 5.53 (5.66) 24 4.71 (7.91) 3.3 % 0.82 [ -2.96, 4.60 ]
Total (95% CI) 230 226 100.0 % -0.46 [ -1.14, 0.23 ]

-10 -5 0 5 10

Analysis 6.4. Comparison 6 Monotherapy - weight of expelled nasal mucus, Outcome 4 Total weight of nasal
mucus over 4-5 days after virus challenge.
Outcome: 4 Total weight of nasal mucus over 4-5 days after virus challenge
Mean Mean
Doyle 1988 12 12.3 (7.9) 15 14.9 (11.8) 49.2 % -2.60 [ -10.06, 4.86 ]
Gaffey 1987a 12 24.3 (18.3) 11 23.5 (25.7) 8.1 % 0.80 [ -17.58, 19.18 ]
Gaffey 1987b 10 8.1 (13) 11 7.7 (8.8) 29.8 % 0.40 [ -9.19, 9.99 ]
Muether 2001 29 27.1 (21.56) 24 19.7 (30.68) 12.9 % 7.40 [ -7.17, 21.97 ]
Total (95% CI) 63 61 100.0 % -0.14 [ -5.37, 5.09 ]

-20 -10 0 10 20

Analysis 7.1. Comparison 7 Monotherapy - subjective severity assessment of rhinorrhoea - all trials,
Outcome 1 First treatment day.
Comparison: 7 Monotherapy - subjective severity assessment of rhinorrhoea - all trials
Outcome: 1 First treatment day
Mean Mean
Eccles 1995 345 2.13 (0.91) 343 2.27 (0.91) 24.4 % -0.14 [ -0.28, 0.00 ]
Gaffey 1988 119 1.8 (0.6) 115 1.9 (0.6) 19.1 % -0.10 [ -0.25, 0.05 ]
Gwaltney 1996 75 0.41 (0.69) 75 0.39 (0.61) 10.4 % 0.02 [ -0.19, 0.23 ]
Gwaltney 1997 113 0.23 (0.43) 112 0.26 (0.53) 28.3 % -0.03 [ -0.16, 0.10 ]
Muether 2001 29 0.17 (0.38) 24 0.17 (0.65) 5.2 % 0.0 [ -0.29, 0.29 ]
Turner 1997 202 1.73 (0.95) 201 1.65 (0.98) 12.7 % 0.08 [ -0.11, 0.27 ]
Total (95% CI) 883 870 100.0 % -0.05 [ -0.12, 0.02 ]

-10 -5 0 5 10

Outcome 2 Second treatment day.
Outcome: 2 Second treatment day
Mean Mean
Eccles 1995 345 1.77 (0.87) 343 1.92 (0.87) 39.6 % -0.15 [ -0.28, -0.02 ]
Gaffey 1988 119 1.4 (0.8) 115 1.5 (0.7) 18.1 % -0.10 [ -0.29, 0.09 ]
Gwaltney 1996 75 0.67 (0.87) 75 0.97 (0.95) 7.9 % -0.30 [ -0.59, -0.01 ]
Gwaltney 1997 113 0.58 (0.74) 112 0.82 (0.85) 15.4 % -0.24 [ -0.45, -0.03 ]
Muether 2001 29 0.79 (1.02) 24 0.46 (0.89) 2.5 % 0.33 [ -0.18, 0.84 ]
Turner 1997 201 1.46 (0.96) 201 1.58 (1.09) 16.6 % -0.12 [ -0.32, 0.08 ]
Total (95% CI) 882 870 100.0 % -0.15 [ -0.23, -0.07 ]

-10 -5 0 5 10

Outcome 3 Third treatment day.
Outcome: 3 Third treatment day
Mean Mean
Eccles 1995 345 1.07 (0.98) 343 1.11 (0.98) 35.3 % -0.04 [ -0.19, 0.11 ]
Gaffey 1988 119 1.1 (0.8) 115 1 (0.8) 18.0 % 0.10 [ -0.11, 0.31 ]
Gwaltney 1996 75 0.59 (0.78) 75 0.85 (0.87) 10.8 % -0.26 [ -0.52, 0.00 ]
Gwaltney 1997 113 0.53 (0.74) 112 0.81 (0.95) 15.3 % -0.28 [ -0.50, -0.06 ]
Muether 2001 29 1.24 (1.08) 24 1 (1.3) 1.8 % 0.24 [ -0.41, 0.89 ]
Turner 1997 194 1.02 (0.98) 200 1.39 (1.05) 18.8 % -0.37 [ -0.57, -0.17 ]
Total (95% CI) 875 869 100.0 % -0.13 [ -0.22, -0.05 ]

-10 -5 0 5 10

Outcome 4 Fourth treatment day.
Outcome: 4 Fourth treatment day
Mean Mean
Berkowitz 1991 48 0.75 (0.9) 48 0.77 (0.9) 6.0 % -0.02 [ -0.38, 0.34 ]
Gaffey 1988 119 0.7 (0.8) 115 0.7 (0.8) 18.6 % 0.0 [ -0.21, 0.21 ]
Gwaltney 1996 75 0.51 (0.69) 75 0.64 (0.69) 16.0 % -0.13 [ -0.35, 0.09 ]
Gwaltney 1997 113 0.27 (0.53) 112 0.48 (0.74) 27.6 % -0.21 [ -0.38, -0.04 ]
Muether 2001 29 0.59 (0.81) 24 0.88 (0.23) 8.2 % -0.29 [ -0.60, 0.02 ]
Turner 1997 191 0.76 (0.88) 196 1.1 (0.95) 23.5 % -0.34 [ -0.52, -0.16 ]
Total (95% CI) 575 570 100.0 % -0.18 [ -0.27, -0.10 ]

-10 -5 0 5 10

Analysis 8.1. Comparison 8 Monotherapy - subjective severity assessment of rhinorrhoea - non sedating
antihistamines, Outcome 1 Fourth treatment day.
Comparison: 8 Monotherapy - subjective severity assessment of rhinorrhoea - non sedating antihistamines
Mean Mean
Berkowitz 1991 48 0.75 (0.9) 48 0.77 (0.9) 18.4 % -0.02 [ -0.38, 0.34 ]
Gaffey 1988 119 0.7 (0.8) 115 0.7 (0.8) 56.7 % 0.0 [ -0.21, 0.21 ]
Muether 2001 29 0.59 (0.81) 24 0.88 (0.23) 25.0 % -0.29 [ -0.60, 0.02 ]
Total (95% CI) 196 187 100.0 % -0.08 [ -0.23, 0.08 ]

-10 -5 0 5 10

Analysis 9.1. Comparison 9 Monotherapy - subjective severity assessment of rhinorrhoea - 1st generation
antihistamines, Outcome 1 First treatment day.
Comparison: 9 Monotherapy - subjective severity assessment of rhinorrhoea - 1st generation antihistamines
Mean Mean
Eccles 1995 345 2.13 (0.91) 343 2.27 (0.91) 32.2 % -0.14 [ -0.28, 0.00 ]
Gwaltney 1996 75 0.41 (0.69) 75 0.39 (0.61) 13.7 % 0.02 [ -0.19, 0.23 ]
Gwaltney 1997 113 0.23 (0.43) 112 0.26 (0.53) 37.4 % -0.03 [ -0.16, 0.10 ]
Turner 1997 202 1.73 (0.95) 201 1.65 (0.98) 16.8 % 0.08 [ -0.11, 0.27 ]
Total (95% CI) 735 731 100.0 % -0.04 [ -0.12, 0.04 ]

-10 -5 0 5 10

antihistamines, Outcome 2 Second treatment day.
Mean Mean
Eccles 1995 345 1.77 (0.87) 343 1.92 (0.87) 49.8 % -0.15 [ -0.28, -0.02 ]
Gwaltney 1996 75 0.67 (0.87) 75 0.97 (0.95) 9.9 % -0.30 [ -0.59, -0.01 ]
Gwaltney 1997 113 0.58 (0.74) 112 0.82 (0.85) 19.4 % -0.24 [ -0.45, -0.03 ]
Turner 1997 201 1.46 (0.96) 201 1.58 (1.09) 20.9 % -0.12 [ -0.32, 0.08 ]
Total (95% CI) 734 731 100.0 % -0.18 [ -0.27, -0.08 ]

-10 -5 0 5 10

antihistamines, Outcome 3 Third treatment day.
Mean Mean
Eccles 1995 345 1.07 (0.98) 343 1.11 (0.98) 43.2 % -0.04 [ -0.19, 0.11 ]
Gwaltney 1996 75 0.59 (0.78) 75 0.85 (0.87) 13.3 % -0.26 [ -0.52, 0.00 ]
Gwaltney 1997 113 0.53 (0.74) 112 0.81 (0.95) 18.7 % -0.28 [ -0.50, -0.06 ]
Turner 1997 202 1.02 (0.99) 201 1.39 (0.99) 24.8 % -0.37 [ -0.56, -0.18 ]
Total (95% CI) 735 731 100.0 % -0.20 [ -0.29, -0.10 ]

-10 -5 0 5 10

Mean Mean
Gwaltney 1996 75 0.51 (0.69) 75 0.64 (0.69) 23.9 % -0.13 [ -0.35, 0.09 ]
Gwaltney 1997 113 0.27 (0.53) 112 0.48 (0.74) 41.1 % -0.21 [ -0.38, -0.04 ]
Turner 1997 191 0.76 (0.88) 196 1.1 (0.95) 35.0 % -0.34 [ -0.52, -0.16 ]
Total (95% CI) 379 383 100.0 % -0.24 [ -0.34, -0.13 ]

-10 -5 0 5 10
Analysis 10.1. Comparison 10 Monotherapy - sneeze counts, Outcome 1 Day 2 after virus challenge.
Comparison: 10 Monotherapy - sneeze counts
Outcome: 1 Day 2 after virus challenge
Mean Mean
Gwaltney 1996 75 2.28 (7.79) 75 3.08 (4.5) 31.4 % -0.80 [ -2.84, 1.24 ]
Gwaltney 1997 113 2.1 (3.51) 112 5.06 (6.56) 68.6 % -2.96 [ -4.34, -1.58 ]
Total (95% CI) 188 187 100.0 % -2.28 [ -3.42, -1.14 ]

-10 -5 0 5 10

Mean Mean
Gwaltney 1996 75 1.95 (3.38) 75 5.61 (7.79) 23.5 % -3.66 [ -5.58, -1.74 ]
Gwaltney 1997 113 1.35 (2.25) 112 3.29 (5.29) 76.5 % -1.94 [ -3.00, -0.88 ]
Total (95% CI) 188 187 100.0 % -2.34 [ -3.27, -1.41 ]

Test for overall effect: Z = 4.93 (P < 0.00001)
-10 -5 0 5 10

Mean Mean
Gwaltney 1996 75 1.83 (3.34) 75 2.81 (4.16) 40.3 % -0.98 [ -2.19, 0.23 ]
Gwaltney 1997 113 0.54 (1.7) 112 1.82 (5.08) 59.7 % -1.28 [ -2.27, -0.29 ]
Total (95% CI) 188 187 100.0 % -1.16 [ -1.93, -0.39 ]

-10 -5 0 5 10
Analysis 11.1. Comparison 11 Monotherapy - subjective severity assesment of sneezing - all trials, Outcome
1 First treatment day.
Comparison: 11 Monotherapy - subjective severity assesment of sneezing - all trials
Mean Mean
Eccles 1995 345 0.93 (0.93) 343 1.04 (0.93) 23.9 % -0.11 [ -0.25, 0.03 ]
Gwaltney 1996 75 0.23 (0.43) 75 0.19 (0.43) 24.4 % 0.04 [ -0.10, 0.18 ]
Gwaltney 1997 113 0.11 (0.32) 112 0.2 (0.53) 35.3 % -0.09 [ -0.20, 0.02 ]
Turner 1997 202 1.17 (0.84) 201 1.32 (0.88) 16.4 % -0.15 [ -0.32, 0.02 ]
Total (95% CI) 735 731 100.0 % -0.07 [ -0.14, 0.00 ]

-10 -5 0 5 10

2 Second treatment day.
Mean Mean
Eccles 1995 345 0.62 (0.82) 343 0.84 (0.81) 35.1 % -0.22 [ -0.34, -0.10 ]
Gwaltney 1996 75 0.28 (0.52) 75 0.55 (0.61) 15.8 % -0.27 [ -0.45, -0.09 ]
Gwaltney 1997 113 0.28 (0.53) 112 0.6 (0.64) 22.0 % -0.32 [ -0.47, -0.17 ]
Muether 2001 29 0.14 (0.32) 24 0.17 (0.47) 10.6 % -0.03 [ -0.25, 0.19 ]
Turner 1997 201 0.74 (0.82) 201 1.16 (0.99) 16.5 % -0.42 [ -0.60, -0.24 ]
Total (95% CI) 763 755 100.0 % -0.26 [ -0.33, -0.19 ]

-10 -5 0 5 10

3 Third treatment day.
Mean Mean
Eccles 1995 345 0.36 (0.74) 343 0.54 (0.74) 43.3 % -0.18 [ -0.29, -0.07 ]
Gwaltney 1996 75 0.36 (0.52) 75 0.76 (0.78) 11.8 % -0.40 [ -0.61, -0.19 ]
Gwaltney 1997 113 0.25 (0.42) 112 0.73 (0.74) 21.4 % -0.48 [ -0.64, -0.32 ]
Muether 2001 29 0.52 (0.65) 24 0.46 (0.77) 3.5 % 0.06 [ -0.33, 0.45 ]
Turner 1997 194 0.54 (0.74) 200 0.9 (0.9) 20.1 % -0.36 [ -0.52, -0.20 ]
Total (95% CI) 756 754 100.0 % -0.30 [ -0.37, -0.22 ]

-10 -5 0 5 10

4 Fourth treatment day.
Mean Mean
Berkowitz 1991 48 0.33 (0.62) 48 0.56 (0.9) 6.6 % -0.23 [ -0.54, 0.08 ]
Gwaltney 1996 75 0.27 (0.43) 75 0.48 (0.69) 18.6 % -0.21 [ -0.39, -0.03 ]
Gwaltney 1997 113 0.16 (0.42) 112 0.42 (0.53) 40.2 % -0.26 [ -0.39, -0.13 ]
Muether 2001 29 0.41 (0.49) 24 0.54 (0.89) 4.0 % -0.13 [ -0.53, 0.27 ]
Turner 1997 191 0.31 (0.59) 196 0.7 (0.83) 30.7 % -0.39 [ -0.53, -0.25 ]
Total (95% CI) 456 455 100.0 % -0.28 [ -0.36, -0.20 ]

-10 -5 0 5 10

Analysis 12.1. Comparison 12 Monotherapy - subjective severity assessment of sneezing - 1st generation
antihistamines, Outcome 1 First treatment day.
Comparison: 12 Monotherapy - subjective severity assessment of sneezing - 1st generation antihistamines
Mean Mean
Eccles 1995 345 0.93 (0.93) 343 1.04 (0.93) 23.9 % -0.11 [ -0.25, 0.03 ]
Gwaltney 1996 75 0.23 (0.43) 75 0.19 (0.43) 24.4 % 0.04 [ -0.10, 0.18 ]
Gwaltney 1997 113 0.11 (0.32) 112 0.2 (0.53) 35.3 % -0.09 [ -0.20, 0.02 ]
Turner 1997 202 1.17 (0.84) 201 1.32 (0.88) 16.4 % -0.15 [ -0.32, 0.02 ]
Total (95% CI) 735 731 100.0 % -0.07 [ -0.14, 0.00 ]

-10 -5 0 5 10

antihistamines, Outcome 2 Second treatment day.
Mean Mean
Eccles 1995 345 0.62 (0.82) 343 0.84 (0.81) 39.2 % -0.22 [ -0.34, -0.10 ]
Gwaltney 1996 75 0.28 (0.52) 75 0.55 (0.61) 17.7 % -0.27 [ -0.45, -0.09 ]
Gwaltney 1997 113 0.28 (0.53) 112 0.6 (0.64) 24.7 % -0.32 [ -0.47, -0.17 ]
Turner 1997 201 0.74 (0.82) 201 1.16 (0.99) 18.4 % -0.42 [ -0.60, -0.24 ]
Total (95% CI) 734 731 100.0 % -0.29 [ -0.37, -0.21 ]

-10 -5 0 5 10

antihistamines, Outcome 3 Third treatment day.
Mean Mean
Eccles 1995 345 0.36 (0.74) 343 0.54 (0.74) 44.9 % -0.18 [ -0.29, -0.07 ]
Gwaltney 1996 75 0.36 (0.52) 75 0.76 (0.78) 12.2 % -0.40 [ -0.61, -0.19 ]
Gwaltney 1997 113 0.25 (0.42) 112 0.73 (0.74) 22.1 % -0.48 [ -0.64, -0.32 ]
Turner 1997 194 0.54 (0.74) 200 0.9 (0.9) 20.8 % -0.36 [ -0.52, -0.20 ]
Total (95% CI) 727 730 100.0 % -0.31 [ -0.38, -0.24 ]

-10 -5 0 5 10

Mean Mean
Gwaltney 1996 75 0.27 (0.43) 75 0.48 (0.69) 20.8 % -0.21 [ -0.39, -0.03 ]
Gwaltney 1997 113 0.16 (0.42) 112 0.42 (0.53) 45.0 % -0.26 [ -0.39, -0.13 ]
Turner 1997 191 0.31 (0.59) 196 0.7 (0.83) 34.3 % -0.39 [ -0.53, -0.25 ]
Total (95% CI) 379 383 100.0 % -0.29 [ -0.38, -0.21 ]

-10 -5 0 5 10

Analysis 13.1. Comparison 13 Monotherapy - side effects, Outcome 1 Side effects : all - all trials.
Comparison: 13 Monotherapy - side effects
Outcome: 1 Side effects : all - all trials
Peto Peto
Berkowitz 1991 6/49 5/50 2.2 % 1.25 [ 0.36, 4.36 ]
Bye 1980 13/56 19/53 5.1 % 0.55 [ 0.24, 1.24 ]
Cowan 1950 25/143 7/76 5.5 % 1.93 [ 0.88, 4.25 ]
Crutcher 1981 14/52 15/54 4.7 % 0.96 [ 0.41, 2.24 ]
Gwaltney 1997 10/113 10/112 4.1 % 0.99 [ 0.40, 2.48 ]
Henauer 1988 7/28 6/35 2.3 % 1.60 [ 0.47, 5.42 ]
Howard 1979 32/133 32/138 10.9 % 1.05 [ 0.60, 1.84 ]
MRC (Part II) 1950 121/579 111/572 41.2 % 1.10 [ 0.82, 1.46 ]
Muether 2001 0/29 2/24 0.4 % 0.11 [ 0.01, 1.75 ]
Tebrock 1973 26/269 15/277 8.4 % 1.84 [ 0.98, 3.48 ]
Turner 1997 56/202 30/201 15.1 % 2.14 [ 1.33, 3.44 ]
Total (95% CI) 1653 1592 100.0 % 1.25 [ 1.04, 1.50 ]

0.005 0.1 1 10 200


Analysis 13.2. Comparison 13 Monotherapy - side effects, Outcome 2 Side effects : all - non-sedating
antihistamines.
Outcome: 2 Side effects : all - non-sedating antihistamines

Berkowitz 1991 6/49 5/50 39.4 % 1.26 [ 0.36, 4.42 ]
Henauer 1988 7/28 6/35 36.3 % 1.61 [ 0.47, 5.49 ]
Muether 2001 0/29 2/24 24.3 % 0.15 [ 0.01, 3.34 ]
Total (95% CI) 106 109 100.0 % 1.12 [ 0.50, 2.51 ]

0.05 0.2 1 5 20

Analysis 13.3. Comparison 13 Monotherapy - side effects, Outcome 3 Side effects : first generation
antihistamines.
Outcome: 3 Side effects : first generation antihistamines

Bye 1980 13/56 19/53 7.9 % 0.54 [ 0.23, 1.25 ]
Cowan 1950 25/143 7/76 4.0 % 2.09 [ 0.86, 5.08 ]
Crutcher 1981 14/52 15/54 5.7 % 0.96 [ 0.41, 2.25 ]
Gwaltney 1997 10/113 10/112 4.8 % 0.99 [ 0.40, 2.48 ]
Howard 1979 32/133 32/138 12.6 % 1.05 [ 0.60, 1.84 ]
MRC (Part II) 1950 121/579 111/572 46.6 % 1.10 [ 0.82, 1.46 ]
Tebrock 1973 26/269 15/277 7.0 % 1.87 [ 0.97, 3.61 ]
Turner 1997 56/202 30/201 11.5 % 2.19 [ 1.33, 3.59 ]
Total (95% CI) 1547 1483 100.0 % 1.25 [ 1.04, 1.52 ]

0.1 0.2 0.5 1 2 5 10


Analysis 13.4. Comparison 13 Monotherapy - side effects, Outcome 4 Side effects : sedation - all trials.
Outcome: 4 Side effects : sedation - all trials
Peto Peto
Berkowitz 1991 0/49 1/50 0.5 % 0.14 [ 0.00, 6.96 ]
Cowan 1950 8/143 2/76 4.4 % 1.97 [ 0.52, 7.44 ]
Eccles 1995 46/345 18/343 29.2 % 2.60 [ 1.56, 4.35 ]
Gaffey 1987b 2/13 3/15 2.1 % 0.74 [ 0.11, 4.96 ]
Gaffey 1988 15/126 13/124 12.5 % 1.15 [ 0.53, 2.53 ]
MRC (Part II) 1950 26/579 35/577 29.0 % 0.73 [ 0.44, 1.22 ]
Tebrock 1973 12/269 4/277 7.8 % 2.88 [ 1.07, 7.79 ]
Turner 1997 28/202 3/201 14.4 % 5.68 [ 2.73, 11.82 ]
Total (95% CI) 1726 1663 100.0 % 1.74 [ 1.32, 2.29 ]

0.05 0.2 1 5 20

Analysis 13.5. Comparison 13 Monotherapy - side effects, Outcome 5 Side effects : sedation - non-sedating
antihistamines.
Outcome: 5 Side effects : sedation - non-sedating antihistamines

Berkowitz 1991 0/49 1/50 11.3 % 0.33 [ 0.01, 8.38 ]
Gaffey 1988 15/126 13/124 88.7 % 1.15 [ 0.52, 2.54 ]
Total (95% CI) 175 174 100.0 % 1.06 [ 0.50, 2.26 ]

0.1 0.2 0.5 1 2 5 10


Analysis 13.6. Comparison 13 Monotherapy - side effects, Outcome 6 Side effects : sedation - first
generation antihistamines.
Outcome: 6 Side effects : sedation - first generation antihistamines

Cowan 1950 8/143 2/76 4.1 % 2.19 [ 0.45, 10.59 ]
Eccles 1995 46/345 18/343 25.9 % 2.78 [ 1.58, 4.90 ]
Gaffey 1987b 2/13 3/15 3.9 % 0.73 [ 0.10, 5.20 ]
MRC (Part II) 1950 26/579 35/577 55.5 % 0.73 [ 0.43, 1.23 ]
Tebrock 1973 12/269 4/277 6.2 % 3.19 [ 1.01, 10.01 ]
Turner 1997 28/202 3/201 4.3 % 10.62 [ 3.17, 35.54 ]
Total (95% CI) 1551 1489 100.0 % 1.90 [ 1.39, 2.59 ]

0.05 0.2 1 5 20

Analysis 13.7. Comparison 13 Monotherapy - side effects, Outcome 7 Side effects : gastro-intestinal.
Outcome: 7 Side effects : gastro-intestinal
Peto Peto
Berkowitz 1991 1/49 0/50 1.5 % 7.54 [ 0.15, 380.14 ]
Cowan 1950 3/143 1/76 5.5 % 1.54 [ 0.19, 12.27 ]
Gaffey 1987b 1/13 0/15 1.5 % 8.62 [ 0.17, 438.70 ]
Gaffey 1988 5/126 1/124 9.0 % 3.84 [ 0.76, 19.32 ]
MRC (Part II) 1950 25/579 19/577 64.6 % 1.32 [ 0.72, 2.42 ]
Muether 2001 0/29 1/24 1.5 % 0.11 [ 0.00, 5.64 ]
Tebrock 1973 7/269 4/277 16.5 % 1.80 [ 0.54, 5.92 ]
Total (95% CI) 1208 1143 100.0 % 1.57 [ 0.97, 2.55 ]

0.02 0.1 1 10 50

Analysis 13.8. Comparison 13 Monotherapy - side effects, Outcome 8 Side effects : sleeplessness.
Outcome: 8 Side effects : sleeplessness
Peto Peto
Cowan 1950 3/143 0/76 25.3 % 4.69 [ 0.43, 51.10 ]
Gaffey 1988 3/126 1/124 37.2 % 2.71 [ 0.38, 19.45 ]
MRC (Part II) 1950 3/579 1/577 37.5 % 2.72 [ 0.38, 19.33 ]
Total (95% CI) 848 777 100.0 % 3.12 [ 0.94, 10.36 ]

0.05 0.2 1 5 20
Analysis 13.9. Comparison 13 Monotherapy - side effects, Outcome 9 Side effect : dry nose.
Outcome: 9 Side effect : dry nose
Peto Peto
Gaffey 1987a 1/12 4/11 12.1 % 0.21 [ 0.03, 1.44 ]
Gwaltney 1996 27/75 13/75 87.9 % 2.58 [ 1.25, 5.31 ]
Total (95% CI) 87 86 100.0 % 1.90 [ 0.97, 3.73 ]

0.02 0.1 1 10 50

Analysis 13.10. Comparison 13 Monotherapy - side effects, Outcome 10 Side effects : headache.
Outcome: 10 Side effects : headache
Peto Peto
Berkowitz 1991 3/49 2/50 6.1 % 1.55 [ 0.26, 9.28 ]
Gaffey 1988 7/126 10/124 20.1 % 0.67 [ 0.25, 1.80 ]
MRC (Part II) 1950 32/579 22/577 65.1 % 1.47 [ 0.85, 2.54 ]
Muether 2001 0/29 1/24 1.3 % 0.11 [ 0.00, 5.64 ]
Tebrock 1973 3/269 3/277 7.5 % 1.03 [ 0.21, 5.14 ]
Total (95% CI) 1052 1052 100.0 % 1.19 [ 0.76, 1.85 ]

0.02 0.1 1 10 50

Analysis 13.11. Comparison 13 Monotherapy - side effects, Outcome 11 Side effects: vertigo, dizziness.
Outcome: 11 Side effects: vertigo, dizziness
Peto Peto
Berkowitz 1991 1/49 1/50 5.0 % 1.02 [ 0.06, 16.55 ]
Cowan 1950 2/143 2/76 9.0 % 0.50 [ 0.06, 4.01 ]
Gaffey 1987b 0/13 1/15 2.5 % 0.15 [ 0.00, 7.87 ]
MRC (Part II) 1950 21/579 13/577 83.5 % 1.62 [ 0.82, 3.20 ]
Total (95% CI) 784 718 100.0 % 1.34 [ 0.72, 2.50 ]

0.02 0.1 1 10 50

Analysis 13.12. Comparison 13 Monotherapy - side effects, Outcome 12 Side effects : dry mouth.
Outcome: 12 Side effects : dry mouth
Peto Peto
Gaffey 1987a 4/10 4/11 14.1 % 1.16 [ 0.21, 6.47 ]
Gaffey 1988 1/126 3/124 10.8 % 0.36 [ 0.05, 2.57 ]
Gwaltney 1996 20/75 16/75 75.1 % 1.34 [ 0.63, 2.82 ]
Total (95% CI) 211 210 100.0 % 1.14 [ 0.60, 2.17 ]

0.05 0.2 1 5 20
Analysis 14.1. Comparison 14 Combination therapy - global evaluation, Outcome 1 Combination therapy -
global evaluation after 2 to 4 days of treatment.
Comparison: 14 Combination therapy - global evaluation
Outcome: 1 Combination therapy - global evaluation after 2 to 4 days of treatment

Galvez 1985 5/22 14/24 54.5 % 0.21 [ 0.06, 0.76 ]
Scavino 1985 2/25 9/23 45.5 % 0.14 [ 0.03, 0.72 ]
Total (95% CI) 47 47 100.0 % 0.18 [ 0.06, 0.49 ]

0.01 0.1 1 10 100


Analysis 14.2. Comparison 14 Combination therapy - global evaluation, Outcome 2 Combination therapy -
global evalution at final evaluation time.
Comparison: 14 Combination therapy - global evaluation
Outcome: 2 Combination therapy - global evalution at final evaluation time

Bye 1980 28/56 49/63 59.8 % 0.29 [ 0.13, 0.63 ]
Galvez 1985 2/22 9/24 20.3 % 0.17 [ 0.03, 0.89 ]
Scavino 1985 0/25 7/23 19.9 % 0.04 [ 0.00, 0.81 ]
Total (95% CI) 103 110 100.0 % 0.21 [ 0.11, 0.42 ]

0.1 0.2 0.5 1 2 5 10


Analysis 15.1. Comparison 15 Combination therapy - side effects, Outcome 1 Side-effects : all.
Comparison: 15 Combination therapy - side effects
Outcome: 1 Side-effects : all

Berkowitz 1989 42/133 29/128 45.2 % 1.58 [ 0.91, 2.74 ]
Bye 1980 6/48 19/53 35.3 % 0.26 [ 0.09, 0.71 ]
Galvez 1985 4/25 0/27 0.9 % 11.51 [ 0.59, 225.67 ]
Lebacq 1994 0/18 0/18 Not estimable
Scavino 1985 3/26 0/23 1.0 % 7.00 [ 0.34, 143.13 ]
Virtanen 1983 25/44 19/48 17.5 % 2.01 [ 0.87, 4.61 ]
Total (95% CI) 294 297 100.0 % 1.33 [ 0.90, 1.96 ]

0.02 0.1 1 10 50

Analysis 15.2. Comparison 15 Combination therapy - side effects, Outcome 2 Side-effects : drowsiness,
hypersomia and excessive sleepiness.
Outcome: 2 Side-effects : drowsiness, hypersomia and excessive sleepiness

Berkowitz 1989 7/133 8/128 30.0 % 0.83 [ 0.29, 2.37 ]
Curley 1988 17/38 23/35 51.3 % 0.42 [ 0.16, 1.09 ]
Galvez 1985 4/25 0/27 1.5 % 11.51 [ 0.59, 225.67 ]
Virtanen 1983 10/44 6/48 17.2 % 2.06 [ 0.68, 6.24 ]
Total (95% CI) 240 238 100.0 % 1.00 [ 0.58, 1.72 ]

0.02 0.1 1 10 50

Analysis 15.3. Comparison 15 Combination therapy - side effects, Outcome 3 Side-effects : dry mouth.
Outcome: 3 Side-effects : dry mouth

Berkowitz 1989 12/133 3/128 36.6 % 4.13 [ 1.14, 15.01 ]
Curley 1988 32/38 19/35 41.1 % 4.49 [ 1.50, 13.45 ]
Virtanen 1983 5/44 2/48 22.3 % 2.95 [ 0.54, 16.05 ]
Total (95% CI) 215 211 100.0 % 4.02 [ 1.89, 8.51 ]

0.05 0.2 1 5 20
Analysis 15.4. Comparison 15 Combination therapy - side effects, Outcome 4 Side-effects : insomnia.
Outcome: 4 Side-effects : insomnia

Berkowitz 1989 8/133 4/128 29.8 % 1.98 [ 0.58, 6.76 ]
Curley 1988 16/38 15/35 70.2 % 0.97 [ 0.38, 2.46 ]
Total (95% CI) 171 163 100.0 % 1.27 [ 0.61, 2.64 ]

0.1 0.2 0.5 1 2 5 10


Analysis 15.5. Comparison 15 Combination therapy - side effects, Outcome 5 Side-effects : gastro-intestinal.
Outcome: 5 Side-effects : gastro-intestinal

Curley 1988 4/38 8/35 94.2 % 0.40 [ 0.11, 1.46 ]
Virtanen 1983 1/44 0/48 5.8 % 3.34 [ 0.13, 84.28 ]
Total (95% CI) 82 83 100.0 % 0.57 [ 0.18, 1.78 ]

0.05 0.2 1 5 20
ADDITIONAL TABLES
Table 1. monotherapy - global evaluation
id results
Crutcher 1981 global assessments in favour of treatment from 48h until day 7 after start of treatment; p = 0.05 (no other data in
paper)
Gwaltney 1997 mean VAS at final evaluation (after 4 days) : with active treatment is 6.2/10; with placebo 5.1/10 (p < 0.01)
Hugenin 1988 number of days until normalisation of general condition: 5.2 (+ -2.3) with placebo and 4 (+-2.12) with active
treatment (p=0.06)
Gaffey 1988 global evaluation score on 5 point scale: active treatment 2.2 (+ -1.1),
placebo 2.1 (+ -1.3) (p = 1)
Berkowitz 1991 global evaluation by physician on 5 point scale at day 4: no significant differences between treatment group but
not further data in paper
Gwaltney 1996 no significant difference between treatment groups on daily global evaluation scores

Table 2. monotherapy - objective assessments of nasal obstruction
id results
Aschan 1974 b proportion of patients with positive rhinomanometric result: clemastine 2/15,
placebo 0/15 (p = 0.46)
Gaffey 1987 mean difference between groups in nasal airflow after first dose of intranasally diphenhydramine 0.12 l/s, and after
second dose 0.09 l/s. Not significant. Standard deviations p-values not mentioned
Doyle 1988 graphical display of inspiratory work/litre by study day shows no differences between group with chlorpheniramine
and group with placebo
Henauer 1988 2 hours after one administration of terfenadine: significant difference in nasal airflow (litre/min) (p = 0.0045)
Table 3. monotherapy - subjective severity assessment of nasal obstruction
id results
Doyle 1988 (1) mean sum of severity scores on day 3 to 6 after virus inoculation: chlorpheniramine 3.2 (+ -1.9), placebo 4.7 (+
-2.9); (p = 0.11);
(2) average days with nasal obstruction: chlorpheniramine 2.4 (+ -1.4); (p = 0.14)
Ectors 1994 mean change in severity score after 2 days of treatment: cetirizine from 1.9 to 0.9, placebo from 2.15 to 1.5 (p = 0.
035) (SEM not mentioned)
Tebrock 1973 (1) proportion of patients with improvement after 1 day: benylin 58/177;
placebo 42/164; (p = 0.15)
(2) proportion of patients with improvement after 2days: benylin 136/177;

placebo 111/164; (p = 0.06)
(3) proportion of patient with disappearance of nasal congestion after 3 days:

benylin 69/177; placebo: 61/164; (p = 0.73)
Table 4. monotherapy - subjective severity assessment of rhinorrhea
id results
Doyle 1988 (1) Sum score over 4 days of treatment. Chlorpheniramine (3.1 (+ -1.7), placebo 4.4 (+ -3), (p = 0.16).
2) mean number of days with rhinorrhea after virus challenge: chlorpheniramine 2.6 (+ -1.3), placebo: 2.9
(+ -1.4); (p = 0.6)
Bye 1980 no significant difference in daily severity scores of rhinorrhea in patients with triprolidine or placebo (numerical
data not in paper)

Table 4. monotherapy - subjective severity assessment of rhinorrhea (Continued)
Ectors 1994 improvement of rhinorrhoea was not significantly larger with cetirizine, although there was a trend in favour
of active treatment after 1.5 days of treatment (numerical data not in paper)
Hugenin 1988 1) number of days until rhinorrhoea severity score was reduced to 50% of initial value: astemizole 3.4 (+ -1.
7), placebo: 5.1 (+ -2); (p=0.001)
2) proportion of children with complete disappearance of rhinorrhoea after 7 days of treatment : astemizole
79% (18/23); placebo 46% (12/27); (p=0.015)
Howard 1979 (1) significantly lower severity score on 18 of 24 time point during 7 days of treatment with chlorpheniramine
(numerical data not in paper)
(2) decrease in severity scores (significance tests not mentioned in paper):

at 8 pm day 1*: with chlorpheniramine decrease is 53.9% - with placebo 46.4%
at 8 pm day 2: chlorpheniramine 69.4%, placebo 60.7%
at day 7: chlorpheniramine 73.5%, placebo 60.7%
* 10 hours after first dose
Sakchainanont 1990 amount of nasal discharge is less after 3 days: with clemastine in 28/48 children, chlorpheniramine 25/48,
placebo 22/47; (p = 0.53)
Henauer 1988 rhinoscopia in 16 patients (8 terfenadine, 8 placebo): 2 hours and 24 hours after the first tablet, visible nasal
secretion were less with terfenadine than with placebo (results only graphically displayed in paper)
Table 5. monotherapy - effect on anterior rhinoscopia
id results
Henauer 1988 graphical display of result of rhinoscopia shows less severe obstruction, redness, swelling, secretion (measured
on a 4 point scale: absent, moderate, mild, severe). No significance tests performed
Saikchananont 1990 swelling of nasal turbinates: improved in 11/48 with clemastine, 9/48 chlorpheniramine, in 10/47 with
placebo. (p = 0.95)
Table 6. monotherapy - subjective severity assessment of sneezing
id results
Doyle 1988 sum score over 4 days of treatment. Chlorpheniramine: 0.1 (+ -0.3), placebo: 1.5 (+ -1.6); (p < 0.01) average number
of days with sneezing. Chlorpheniramine: 0.1 (+ -0.3), placebo: 1.3 (+ -1.3); (p < 0.01)
Gaffey 1988 severity scores recorded on 7 time points i.e. once every 12 hours during 3.5 days. No significant difference between
treatment groups (numerical data not in paper)
Ectors 1994 improvement of sneezing was not significantly larger with cetirizine, although there was a trend in favour of active
treatment after 1.5 days of treatment (numerical data not in paper)

Table 6. monotherapy - subjective severity assessment of sneezing (Continued)
Howard 1979 (1) significantly lower severity scores on all 24 time points during 7 days of treatment (numerical data not available)
(2) % decrease in severity scores (significance tests not mentioned in paper):

at 10 pm day 1*: with chlorpheniramine decrease is 66%, with placebo 56.3%
at 10 pm day 2: with chlorpheniramine decrease is 88.4%, with placebo 69.6%
* 12 hours after first dose
Bye 1980 significant larger reduction of mean severity scores in patients with tripolidine. (Numerical data not in paper)
Table 7. number of trials recording side-effect
side-effect number of trials
all 12
sedation 9
gastro-intestinal complaints 6
dizziness, vertigo 4
headache 4
sleeplessness 3
dry mouth 3
dry nose 2
muscular pain 1
temperature rise 1
dry eyes 1
dry throat 1
dry mucosa 1
nasal burning 1
bleeding site in nose 1
depression 1
urinary complaints 1

Table 8. combination therapy - global evaluation - data not entered in meta-analysis
identification results
Berkowitz 1989 (1) overall response evaluated by physicians on a 4 point scale : day 3 p = 0.01, day 5 p = 0.02 in favour
of active treatment
(2) overall response evaluated by patients on a 4 point scale : day 3 p = 0.02, in favour of active treatment
no further data available
Thackray 1978 number of patients rating the formulation as good, very good or excellent on the morning after one
dose the night before :
n = 58
Active treatment : 35/58 placebo : 25/58 p < 0,05
Blanco de la Mora 2000 Comparison of severity ratings on the third day of treatment between treatment groups: results are graphical
displayed and summarized in a table. It is however not clear what is presented in the table.
On the graphs, p- values are mentioned when there is a statistical significant difference:
for general unwell feeling : there is no significant difference
Table 9. combination therapy - effect on nasal patency
id results
Aschan 1974 a (1) promethazine+efedrine : positive manometric result (pmr)10/15; placebo : pmr 0/15. (p < 0.001)
1974 c (2) clemastine+phenylpropanolamine : pmr: 14/15, placebo : pmr 0/15 (p < 0.000001)
Lebacq 1994 Nasal resistance in percent of pre-treatment value.

Placebo (P) (n = 6) vs combination 1 (A1) (n = 6) vs combination 2 (A2) (n = 6)
Adults : 1/2 h post dose : P 116 % A1 61% (p < 0.05)* A2 106%
1 h post dose : P 96% A1 52% (p < 0.05)* A2 96%
2 h post dose : P 100% A1 58% (p < 0.05)* A2 81%
4 h post dose : P 103% A1 77 % A2 83%
6.5 h post dose : P 100 % A1 72% A2 77%
11h post dose : P 96 % A1 69 % A2 76%
*significantly different from placebo
children:
1/2 h post dose : P 96 % A1 63% A2 115%
1 h post dose : P 68% A1 70% A2 99%
2 h post dose : P 60% A1 75% A2 112%
4 h post dose : P 103% A1 77 % A2 83%
6.5 h post dose : P 64 % A1 78% A2 97%
10 h post dose : P 65 % A1 72 % A2 99%
no significant differences

Table 10. combination therapy - subjective assessment of severity of nasal congestion
id results
Virtanen 1983 Graphical presentation of mean severity score of nasal obstruction registered during 10 days (treatment
on first 5 days) shows no significant difference between treatment groups.
No further data available.
Hutton 1991 Effect is expressed as severity score changes and presented as z-scores : negative z-score means less than
average improvement, positive z-score means more than average improvement.
z-score on congested and runny nose : active treatment -0.166, placebo : + 0.194 - difference not
significant
Lebacq 1994 Severity assessment is presented as median of 6 scores on a 3 point scale. There was no difference between
treatment groups. We show (as example) results of 1 evaluation point (after 2 hours of intake of medication)
.
median score median score

1. adults : placebo (n = 6) 2 2.children : placebo(n = 6) 2.5
A 1 (n=6) 2 A1 (n=6) 1.5
A2 (n=6) 2 A2 (n=6) 2
A1 = combination 1, A2 = combination 2
Clemens 1997 41/84 responses report improvement of nasal congestion 2 hours after intake of active treatment
40/79 after intake of placebo
p = 0.94
Curley 1988 1.Graphical display of mean severity scores show a significant difference on
day 2 : p = 0.01
day 3 : p = 0.01
day 4 : p = 0.05
day 5 : p = 0.01
No further data available.
2. prevalence of nasal obstruction after 14 days of treatment : active treatment 6/38, placebo 20/35. p <
0.001
Berkowitz 1989 mean scores active treatment placebo

day 1 1.8 2.1
day 2 1.7 1.9 p < 0.05
day 3 1.4 1.7 p < 0.05
day 4 1.3 1.6 p < 0.05
day 5 1.2 1.5 p < 0.05
p <= 0.05 for all presented days
Bye 1980 Severity score significantly reduced on day 1
dose the night before :
n = 63
Active treatment : 44/63 placebo : 29/63 p < 0,05

Table 10. combination therapy - subjective assessment of severity of nasal congestion (Continued)
Blanco de la Mora 2000 Comparison of severity ratings on the 3rd day and 5th of treatment between treatment groups: results are
graphical displayed and summarized in a table. It is however not clear what is presented in the table.
On the graphs, p- values are mentioned when there is statistical significant difference:
for nasal congestion p = 0.041
Table 11. combination therapy - effect on result of anterior rhinoscopia
Lebacq 1994 rhinoscopia result is presented as median of 6 scores on a 3 point scale. There was no difference between treatment
groups. We show (as example) results of 1 evaluation point (after 2 hours of intake of medication).
median score median score

1. adults: placebo (n = 6) 2 2.children : placebo (n = 6) 1.5
A 1 (n = 6) 2 A1 (n = 6) 1
A2 (n = 6) 2 A2 (n = 6) 1.5
A1 = combination 1, A2 = combination 2
Table 12. combination therapy -subjective severity assessment of rhinorrhoea
id results
Hutton 1991 (1) Effect is expressed as severity score changes and presented as z-scores: negative z-score means less
than average improvement, positive z-score means more than average improvement.
z-score on congested and runny nose : active treatment -0.166, placebo : + 0.194 - difference not
significant
(2) number of parents reporting improvement on runny or congested nose:
placebo 19/24
active treatment 16/30
p = 0.05
Clemens 1997 42/83 responses report improvement of runny nose 2 hours after intake of active treatment
46/80 after intake of placebo
p = 0.48
Virtanen 1983 Graphical presentation of mean severity score of nasal discharge registered during 10 days (treatment on
first 5 days) shows no significant difference between treatment groups - except for day (p < 0/05).
No further data presented.
Curley 1988 1.Graphical display of mean severity scores show a significant difference on
day 2: p = 0.05
day 3: p = 0.01
no further data presented
2. prevalence of nasal discharge after 14 days :
active treatment 14/38, placebo 12/35 p = 0.82
Table 12. combination therapy -subjective severity assessment of rhinorrhoea (Continued)

day 1 1.8 1.9
day 2 1.5 1.8 p < 0.05
day 3 1.4 1.5
day 4 1.2 1.4 p < 0.05
day 5 1.1 1.3
Bye 1980 Severity score of nasal discharge : not significantly more reduced with active treatment than with placebo
dose the night before:
n = 55
Active treatment : 35/55 placebo : 29/55 p < 0.05
Blanco de la Mora 2000 Comparison of severity ratings on the third day of treatment between treatment groups: results are graphical
displayed and summarized in a table. It is however not clear what is presented in the table.
On the graphs, p- values are mentioned when there is statistical significance:
for anterior rhinorrhoea p = 0,014
Table 13. combination therapy - effect on subjective severity of sneezing
id results
Bye 1980 Sneezing score is significantly more reduced on day 2, 3 and 4 in the active treatment group than in the placebo
group
Virtanen 1983 Graphical presentation of mean severity score of sneezing registered during 10 days (treatment on first 5 days)
shows a significant difference between treatment groups on day 2 (p < 0.05), day 3 (p < 0.001), day 4 (p < 0.01),
day 5 (p < 0.001), day 6 (p < 0.01), day 7 (p < 0.01), day 8 (p < 0.05)

day 1 0.9 1
day 2 0.6 0.9 p < 0.05
day 3 0.5 0.7 p < 0.05
day 4 0.3 0.6 p < 0.05
day 5 0.3 0.5 p < 0.05
Thackray 1978 number of patients rating the formulation as good, very good or excellent on the morning after one dose the
night before :
n = 30
Active treatment : 25/55 placebo : 20/55 p = 0.14

Table 14. combination therapy - number of trials reporting a certain side-efectt
side-effect number of trials
all side-effects 6
dry mouth 3
drowsiness/ hypersomnia 2
insomnia 2
gastro-intestinal upset 2
dizziness 1
rash 1
nervousness 1
headache 1
palpitations 1
Table 15. combination therapy - side-effects - data not in meta-analyses
side-effect id result
dizziness Curley 1988 active treatment : 13 / 38, placebo : 10/35; p = 0.6
rash Curley 1988 active treatment : 1 / 38, placebo : 0/35; p = 0.33
nervousness Berkowitz 1989 active treatment : 5 / 133,placebo : 3/128; p = 0.51
headache Virtanen 1983 active treament : 8 / 44 ; placebo : 11/48; p = 0.25
palpitations Virtanen 1983 active treatment : 1 / 44; placebo : 0/48; p = 0.29
giddiness/drowsiness Thackray 1978 crossover design : side effect reported by 7 patients when taking active treatment,
and by 4 when taking placebo
drowsy or sleepy Blanco de la Mora 2000 not more frequent with active treatment - numbers not mentioned

Table 16. Product/effect/method of infection
id product global nasal rhinorrhoea sneezing method of in- Age of partic- generation
obstruction fection ipant
Berkowitz terfenadine neg neg neg neg comm. Acq. adult non-sed
1991
Gaffey 1988 terfenadine neg neg neg neg comm. Acq. adult non-sed
Howard chlorpheni- neg pos pos comm. Acq. 1st generation

1979 ramine
Hutton brompheni- neg neg neg comm. Acq. 6mo-5y 1st generation
1991 ramine +
DC
Hugenin cetirizine pos pos comm. Acq. 2y-15y non-sed

1988
Bye 1980 tripolidine pos neg neg pos comm. Acq. adult 1st generation
Bye 1980 tripolidine + pos pos neg pos comm. Acq. adult 1st generation
DC
Berkowitz loratadine + pos pos pos pos comm. Acq. adult non-sed
1989 DC
Turner 1997 clemastine pos pos comm. Acq. adult 1st generation
Curley 1988 pos pos comm. Acq. adult 1st generation

dexbrompheni-
ramine
Virtanen dexchlor- neg pos pos comm. Acq. adult 1st generation
1983 pheni-
ramine +
DC
Eccles 1995 doxylamine pos pos comm. Acq. adult 1st generation
Clemens brompheni- neg neg comm. Acq. 6mo-5y 1st generation

1997 ramine +
DC
Saikchain- chlorpheni- neg comm. Acq. 6mo-5y 1st generation

ont 1990 ramine
Gwaltney clemastine neg neg pos pos exp adult 1st generation
1996

Table 16. Product/effect/method of infection (Continued)
Gwaltney brompheni- pos pos pos pos exp adult 1st generation
1997 ramine
Ectors 1994 cetirizine pos neg neg exp adult non-sed
Doyle 1998 chlorpheni- neg neg pos exp adult 1st generation
ramine
Muether loratadine neg neg neg exp adult non-sed

2001
Lorriman anstistin neg Comm.Acq. adult 1st generation

1950
Tebrock benadryl neg neg Comm.Acq. adult 1st generation

1973
Cowan neg Comm.Acq. adult 1st generation

1950 phenidramine
Henauer terfenadine neg Comm.Acq. adult non-sed

1988
Cowan tripenlen- neg Comm.Acq. adult 1st generation

1950 namine
Galvez 1985 azatadine + pos Comm.Acq. >6 1st generation

DC + cough
Scavino azatadine + pos Comm.Acq. >6 1st generation

1985 DC+ cough
Crutcher chlorpheni- pos Comm.Acq. adult 1st generation

1981 ramine
MCR 1950 thonzy- pos Comm.Acq. adult 1st generation

lamine
Saikchain- clemastine neg Comm.Acq. 6mo-5y 1st generation

ont 1990
Lebacq carbinoxam- neg Comm.Acq. adult + child 1st generation

1994 ine+DC (>6)
Lebacq pheni- neg Comm.Acq. adult+child 1st generation

1994 ramine+mepiramine+DC (>6)
Gaffey 1987 chlorpheni- exp adult 1st generation

ramine

Table 16. Product/effect/method of infection (Continued)
Gaffey 1987 diphenhy- exp adult 1st generation

dramine
Blanco de la lorata- neg pos pos pos Comm.Acq. adult non-sed

Mora 2000 dine+DC+cough
Gwaltney chlorpheni- neg neg neg neg exp adult 1st generation
2002 ramine +
NSAID
Thackray doxy- pos pos pos Comm.Acq. adult 1st generation

1978 lamine+paracetamol+DC+cough
Aschan promet- pos comm.Acq. adult 1st generation

1974 a hazine+DC
Aschan clemastine neg Comm.Acq. adult 1st generation

1974 b
Aschan clemastine + pos Comm.Acq. adult 1st generation

1974 c DC
WHATS NEW
Last assessed as up-to-date: 27 May 2003.
Date Event Description
16 September 2008 Amended Converted to new review format.
HISTORY
Protocol first published: Issue 4, 1998
Review first published: Issue 3, 2003

CONTRIBUTIONS OF AUTHORS
H. Campell and H. Mc Kinnon wrote the protocol, performed a first search and selected papers.
M. Lemiengre selected papers, assessed the quality of selected papers and assisted with data extraction.
A. De Sutter selected papers, did the quality assessment, data extraction, data entering and wrote the text of review.
DECLARATIONS OF INTEREST
This review is financed by the Department of General Practice and Primay Health Care of the University of Ghent (Belgium).
SOURCES OF SUPPORT
Internal sources
Department of General Practice and Primary Health Care - University of Ghent - Belgium, Belgium.
External sources
No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)

Common Cold [ drug therapy]; Histamine H1 Antagonists [ therapeutic use]; Histamine H1 Antagonists, Non-Sedating [therapeutic
use]; Randomized Controlled Trials as Topic
MeSH check words

Humans


Antihistamin in Common Cold

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Antihistamin in Common Cold

Uploaded by

Copyright:

Available Formats

Antihistamines for the common cold (Review)

De Sutter AIM, Lemiengre M, Campbell H

Antihistamines for the common cold (Review)

Antihistamines for the common cold (Review) ii

Antihistamines for the common cold (Review) iii

Antihistamines for the common cold

An IM De Sutter1 , Marc Lemiengre1 , Harry Campbell2

University of Edinburgh, Edinburgh, UK

Editorial group: Cochrane Acute Respiratory Infections Group.

PLAIN LANGUAGE SUMMARY

BACKGROUND by hand to face transfer from fomites. Symptoms arise from an

Why it is important to do this review Types of interventions

OBJECTIVES Types of outcome measures

Antihistamines for the common cold (Review) 3

Assessment of risk of bias in included studies

Antihistamines for the common cold (Review) 4

Antihistamines for the common cold (Review) 5

Antihistamines for the common cold (Review) 6

(a) Systematic review

Antihistamines for the common cold (Review) 7

Antihistamines for the common cold (Review) 8

Antihistamines for the common cold (Review) 9

Antihistamines for the common cold (Review) 10

Antihistamines for the common cold (Review) 11

Antihistamines for the common cold (Review) 12

Antihistamines for the common cold (Review) 13

Antihistamines for the common cold (Review) 14

Antihistamines for the common cold (Review) 15

Antihistamines for the common cold (Review) 16

Antihistamines for the common cold (Review) 17

Antihistamines for the common cold (Review) 18

In adolescents and adults the situation regarding combination

Antihistamines for the common cold (Review) 21

Antihistamines for the common cold (Review) 22

Characteristics of included studies [ordered by study ID]

Participants -adult volunteers

Interventions promethazine chloride 15 mg+ efedrine 10 mg

Outcomes rhinomanometric changes in nasal patency

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Participants -adult volunteers

Antihistamines for the common cold (Review) 23

Outcomes rhinomanometric changes in nasal patency

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Participants -adult volunteers

Interventions clemastine 1 mg + phenylpropanolamine 50 mg retarded

Outcomes rhinomanometric changes in nasal patency

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Antihistamines for the common cold (Review) 24

Methods a. SF 12/13 J 2-2-1

Participants -adult volunteers -setting: multicenter trial, recruitment: not clear

Interventions loratadine 5mg /pseudoefedrine 120 mg 2x/d

Outcomes 1.overall response according to physician on day 3 and 5

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Methods a. SF11 J1-2-1

Participants -age 12 to65

Antihistamines for the common cold (Review) 25

Interventions terfenadine 60 mg 2x/d

Item Authors judgement Description

Allocation concealment? Yes A - Adequate

Participants -age: 18-45-setting: hospital research center