Instructions
In this assignment, you will apply what you learned about the scientific method to evaluate the validity of two different health claims. There are three file attachments for this assignment. There you will find and read the GetAnAnswerNow.com posting, a scientific article about zinc’s effect on colds, and a table with a short essay question for you to fill out.
Read the Hemila, 2011, a published scientific paper, and the GetAnAnswerNow.com health claim, which is a fictional posting on the internet.
Fill out the table titled “Evaluating Health Claims” to help you determine how scientific each claim is. The table will help you to decide:
Which steps of the scientific method were used?
Which steps of the scientific method were not used?
Do you feel that the scientific method was sufficiently used in each article to give credibility to its claims? Why or why not?
Answer the short essay question below the table and save the completed assignment to your computer and upload it as a Word file to the Assignment drop box titled “Evaluating Health Claims.”
Please, see attached Rubric to make sure that you include all items that will be graded.
Attachments
Hemila, 2011 Zinc’s Effect on Colds.pdf(1.34 MB) GetAnAnswerNow.com Posting.htm(40.05 KB) Evaluating Health Claims Table.docx(13.24 KB) A2 Rubric.png(306.5 KB)
Evaluating Health Claims Assignment
Please fill out the table below with information from the GetAnAnswerNow.com posting and the scientific article about zinc’s effects on colds. Some entries have been filled in for you. Give your overall evaluation of these two health claims by answering the question below the table. Save the completed document as a Word file and upload it to the Evaluating Health Claims Assignment drop box.
GetAnAnswerNow.com Posting
Zinc’s Effects on Colds Article
What was the dependent variable (what was it that the author of the article says “depends” on something else)? For example, you getting wet when you step outside “depends” on whether it is raining outside.
Duration of a cold
What was the independent variable (what was it that the author of the article says something else “depends” on)? For example, you getting wet (from a pool or a shower) doesn’t affect whether it’s raining outside.
Dose of zinc
What was the hypothesis (what did the author set out to test BEFORE the claim was made)?
Missing – None was stated before testing and a conclusion was made
What was the conclusion?
Zinc doses over 75 mg per day have a significant effect in shortening the duration of colds
Evidence that this was a controlled experiment (how did the author prove that other factors that could give false results or an incorrect conclusion were eliminated?
How do you feel about the sources that were used to make each claim (literature used to carry out background research, design the experiment, or interpret results)?
There are no references at all
How do you feel about the level of peer-review for each claim (how many experts in the field reviewed the article before it was published)?
This was published in a scientific journal and has peer-reviewed status
How do you feel about the credibility of each of these two health claims based on the authors’ use of the scientific method (or lack thereof)? Use your table to support your conclusions. Why is the scientific method important in humans’ efforts in gaining scientific knowledge? Please answer these questions in a well-constructed paragraph with at least 5 meaningful sentences.
The Open Respiratory Medicine Journal, 2011, 5, 51-58 51
1874-3064/11 2011 Bentham Open
Open Access
Zinc Lozenges May Shorten the Duration of Colds:
A Systematic Review
Harri Hemilä*
Department of Public Health, University of Helsinki, Helsinki, Finland
Abstract: Background: A number of controlled trials have examined the effect of zinc lozenges on the common cold but
the findings have diverged. The purpose of this study was to examine whether the total daily dose of zinc might explain
part of the variation in the results.
Methods: The Medline, Scopus and Cochrane Central Register of Controlled Trials data bases were searched for placebo-
controlled trials examining the effect of zinc lozenges on common cold duration. Two methods were used for analysis: the
P-values of the trials were combined by using the Fisher method and the results of the trials were pooled by using the
inverse-variance method. Both approaches were used for all the identified trials and separately for the low zinc dose and
the high zinc dose trials.
Results: Thirteen placebo-controlled comparisons have examined the therapeutic effect of zinc lozenges on common cold
episodes of natural origin. Five of the trials used a total daily zinc dose of less than 75 mg and uniformly found no effect.
Three trials used zinc acetate in daily doses of over 75 mg, the pooled result indicating a 42% reduction in the duration of
colds (95% CI: 35% to 48%). Five trials used zinc salts other than acetate in daily doses of over 75 mg, the pooled result
indicating a 20% reduction in the duration of colds (95% CI: 12% to 28%).
Conclusions: This study shows strong evidence that the zinc lozenge effect on common cold duration is heterogeneous so
that benefit is observed with high doses of zinc but not with low doses. The effects of zinc lozenges should be further
studied to determine the optimal lozenge compositions and treatment strategies.
Keywords: Meta-analysis, randomized controlled trials, respiratory infections, zinc.
INTRODUCTION
Zinc has various effects on the immune system and its
deficiency increases the risk of infections [1,2]. In develop-
ing countries, there is evidence that zinc supplementation
may reduce the risk of the common cold and pneumonia in
children [2-4]. Although such studies indicate that zinc plays
an important role in the immune system, those findings
cannot be extrapolated to the developed countries where
there is no wide spread zinc deficiency. For example, in
France and in the UK, multivitamin-mineral tablets
containing 15 or 20 mg/day of zinc had no effect on the
incidence of respiratory infections of elderly people [5,6].
Interest in zinc lozenges (tablets intended to be dissolved
slowly in the mouth) for treating the common cold started
from the serendipitous observation that a cold of a 3-year-old
girl with leukemia disappeared when she dissolved a
therapeutic zinc tablet in her mouth instead of swallowing it
[7]. This finding led to a series of controlled trials which
have produced conflicting results. The composition of zinc
lozenges has varied and some of them contained substances
which bind zinc ions tightly. Therefore, a low level of free
zinc ions has been considered as one potential factor that
might explain divergence in the results [8-15]. The mode of
*Address correspondence to this author at the Department of Public Health,
University of Helsinki, Mannerheimintie 172, POB 41, Helsinki, FIN-00014
Finland; Tel: +358-9-191 27573; Fax: +358-9-191 27570;
E-mail: [email protected]
action of zinc in the oral cavity is not known. However, the
fundamental questions in evaluating a potential treatment
should be efficacy, safety and cost, whereas biological
explanations and the effects on surrogate outcomes should be
secondary issues [16-18].
The purpose of this systematic review is to examine the
relationship between the total daily dose of zinc from the
lozenges and the effect of the zinc lozenges on the duration
of colds in patients who had natural common cold infections.
METHODS
Search of the Trials
Ovid MEDLINE (November 24, 2010) was searched
using the free search terms “zinc” and “lozenge$” which
retrieved 67 records. The same search terms were used for
SCOPUS (November 24, 2010; 107 records) and for the
Cochrane Central Register of Controlled Trials (CENTRAL;
November 24, 2010; 20 records). No language restrictions
were used in the searches. The reference lists of the trials and
reviews identified were also perused.
This systematic review was restricted to trials examining
the therapeutic effect of zinc lozenges on natural common
cold infections. As an inclusion criterion, a concurrent
placebo group was required, because clinically relevant
common cold outcomes are largely subjective, and explicitly
different interventions (i.e., no placebo in one arm) might
bias the comparison. Studies with adults and children were
both included. Rather than exclude non-randomized trials,
52 The Open Respiratory Medicine Journal, 2011, Volume 5 Harri Hemilä
their influence was considered in a sensitivity analysis.
Eleven publications fulfilling the inclusion criteria were
identified [7,19-28] (Table 1, see Supplementary Material 1
for a flow diagram of the search and Supplementary Material
2 for a summary of the main characteristics of the included
trials). One publication reported three zinc lozenge arms
which were compared with one placebo arm [23], so that the
number of identified zinc lozenge vs placebo comparisons
was 13 (Table 1). One zinc lozenge study was excluded
because the lozenge was used with a nasal spray and thus the
comparison was not specific to the lozenge [29]. No protocol
was written for this systematic review.
To confirm that there are no further trials in addition to
those listed in Table 1, a cited reference search was also
carried out (Web of Science, November 24, 2010) using the
11 identified publications as cited references, because
inaccuracy in coding might hamper the identification of
relevant trials in MEDLINE, SCOPUS and CENTRAL.
Since all new trials on a given topic most probably refer to
one or more earlier trials on the same topic, this provides a
further approach for searching the literature. No additional
trials were identified by screening the 269 publications that
cited the zinc lozenge reports of Table 1.
Calculation of the Daily Zinc Dosage
The total daily dose of elemental zinc from the lozenges
was calculated as the product of the zinc dose per lozenge
and the counted or planned number of lozenges per day
(Table 1; see Supplementary Material 2 for the calculat-
ions). In six trials, the number of lozenges was counted [20-
22, 24-26]. In the other trials, the usage recommended was
the basis for the calculation of the total zinc dosage; for
example, description of the dosage as “every 2 hr awake”
was interpreted as 9 times per day.
Statistical Methods
Some earlier reviews on the effect of zinc lozenges on
common cold symptoms calculated the effect of zinc on
common cold duration on the absolute scale, i.e., as the
difference in days in the cold duration [11,13,14]. However,
Table 1 shows a substantial variation in the duration of colds in
the placebo groups, from 5.1 days [22] to 9.0 days [27] and 10.8
days [7]. Although part of this variation is evidently caused by
random variation, it is also caused by actual variations in the
severity of disease in different patient groups and in differences
in outcome definitions. In this study, the relative effect of zinc
on the common cold duration was calculated in percentages,
because the relative effect partly adjusts for the variations
between patient groups and outcome definitions. Previously, the
calculation of relative effect instead of the absolute effect led to
stronger evidence that vitamin C supplementation decreases the
duration of the common cold [30,31]. Therefore, the relative
effect is used in the Cochrane review on vitamin C and the
common cold [32].
Two different approaches were used to evaluate the
findings of the zinc lozenge trials: 1) combining the P-values
by using the Fisher method [33,34] and 2) pooling the study
results by using the RevMan program (version 5) [35].
Table 1. Effect of Zinc Lozenges on Common Cold Episodes of Natural Origin
Study [Ref.] No. of Participants
Zn Dose
Per Day (mg)
a
Average Duration of Colds (Days)
b
Zn/Placebo
The Effect of Zn
P
b
(1-Tail)
–2 ln(P)
Eby et al.1984 [7] 65 207 3.9/10.8c -64%c 0.0005c 15.2
Smith et al.1989 [19] 110 207
5.9/6.3d
5.5/6.9d
-22%d
0.5d
0.01d
1.4
Godfrey et al. 1992 [20] 73 192 4.9/6.1 -21% 0.024 7.4
Prasad et al. 2008 [21] 50 92 4.0/7.1 -44% 6 10–13 56.3
Petrus et al. 1998 [22] 101 89 3.8/5.1 -26% 0.0033 11.4
Turner at al. A 2000 [23] 139 80 6.0/5.5 0.5 1.4
Mossad et al.1996 [24] 99 80 4.4/7.6 -42% 0.0005 15.2
Prasad et al. 2000 [25] 48 80 4.5/8.1 -44% 2 10–9 40.0
Turner et al. B 2000 [23] 139 69 5.5/5.5 0.5 1.4
Douglas et al. 1987 [26] 58e 64 12.1/7.7 0.96 0.1
Macknin et al. 1998 [27] 247 45 9.0/9.0 0.5 1.4
Weismann et al. 1990 [28] 130 45 7/6 0.5 1.4
Turner et al. C 2000 [23] 143 30 6.0/5.5 0.5 1.4
aCalculation of the daily dose of zinc: see Supplementary Material 2.
bThe outcome is the mean or median of common cold duration, except when otherwise stated. The P-values were recalculated when appropriate data was reported in the paper.
cEby et al. [7] did not report the mean or median duration, but estimated the time at which half of the participants were cured from an exponential fit of the results. The P-value at this
table was calculated by using the Fisher exact test for the number of participants reporting no symptoms after the 7-day trial: 32/37(86%) and 13/28(46%) in the zinc and placebo
groups, respectively.
dSmith et al. [19] reported that “subjects taking zinc gluconate had lower severity scores than those in the corresponding placebo group on days 4 to 7 of treatment. This difference is
statistically significant (P = 0.02).” From Smith et al.’s fig. 2, the days needed for 80% reduction in the severity score, which occurred in the 4 to 7 day time range, was measured
thereby transforming the effect to the time scale for this table. The upper line (5.9/6.3) gives the interpolated time point when 40% of participants had become asymptomatic from
Smith et al.’s fig. 1; the placebo participants were not followed until half of them had become asymptomatic. To be conservative, P = 0.5 was used for calculating the –2 log(P), and
not the small P-value corresponding to the difference in severity scores on days 4 to 7.
eThe number of treatment courses was 63; some of the 58 participants had more than one cold episode.
Zinc Lozenges and the Common Cold The Open Respiratory Medicine Journal, 2011, Volume 5 53
The P-values of Table 1 were combined by using the
Fisher method, which is based on the relation that –2 log(P)
follows the 2-distribution with 2 degrees of freedom, with
the P-value given in the 1-tailed form [33,34]. Thus, the
–2 log(P) values for all selected trials (N trials) are added,
and the total follows the 2-distribution with N 2 degrees of
freedom, which gives the combined P-value for all the N
trials. When appropriate data was published, the accurate
P-values were calculated. For trials for which the P-value
was not reported and could not be calculated, P = 0.5 was
used, which conservatively assumes equality between the
zinc lozenge and the placebo. Extracted or derived P-values
are described in Supplementary Material 2. The combined
P-values for selected groups of trials are calculated in Table 2.
Table 2. The Effect of Zinc Lozenges on the Duration of the
Common Cold: Combining the P-Values of the
Placebo-Controlled Trials
Trials Being Combined No. of Trials
2
df P
All trials 13 154.0 26 10–19
Low Zn dose (<75 mgday) 5 5.7 10 0.8 High Zn dose (>75 mg/day) 8 148.3 16 10–22
Zn-acetate [21,22,25] 3 107.7 6 10–20
not Zn-acetate [7,19,20,23,24] 5 40.6 10 10–5
The P-values of the individual trials are combined by using the Fisher method (see the
Methods section). The combined 2 value is calculated from the –2 ln(P) values on the
right side of Table 1. The combined P-values are separately calculated for low dose and
high dose trials. Finally, the high dose trials are divided to those which used zinc
acetate and to those which used zinc salts other than acetate.
The benefit of the Fisher method of combining P-values
is that it can be used for results that are reported on different
scales and when limited data is available [33,34]. For
example, if one trial reports the duration with its standard
deviation (SD) and another trial reports the number of
participants who had colds lasting over 7 days, both of them
measure the effect on common cold duration, but on
different scales. Although no combined effect estimate can
be calculated for such trials, the P-values of those two trials
can be combined by using the Fisher method. Furthermore, if
there is no difference between the study groups e.g. on the
basis of considerable overlap in the survival graphs – even
though mean and SD are not reported – the study can be
included without making any assumptions about the mean
and SD, since the lack of difference corresponds to P(1-tail)
= 0.5. Some of the zinc lozenge trials did not report the mean
duration of colds and its SD, but they reported the P-values
for the comparison of the zinc and placebo groups. For these
reasons, the Fisher method was used as one approach to test
whether there is a difference between zinc and placebo
groups.
A forest plot (Fig. 1) is an efficient way to show the
results of several trials, and it was used as a second
approach. However, this approach needs the mean and SD
values for the zinc and placebo groups. Only three zinc
lozenge studies reported the SD values [21,22,25]. One study
reported the t-value for the comparison [20] and another
reported the P-value [26], and the corresponding SD-values
were calculated. Nine comparisons were reported as survival
graphs, i.e. the number of participants who remained ill or
were recovered as a function of time [7,19,23-25,27,28].
These graphs were measured and transformed to the
distribution of the duration of colds, which yielded estimates
of the mean and SD (Supplementary Material 3). In the
analysis of the graphs, several imputations were needed,
because the graphs usually did not continue until all patients
were recovered. Since the forest-plot analysis required a
number of subjective decisions, the Fisher method (above)
provided a useful parallel method, because it required less
subjective decisions. Nevertheless, sensitivity analyses
showed that the conclusions of Fig. (1) are robust to
variation in the imputation approach (Supplementary
Material 3). The forest plot (Fig. 1) was calculated by using
the RevMan program of the Cochrane Collaboration (version
5), using the inverse-variance fixed-effect option [35]. The
heterogeneity between trials was assessed by using the 2 and
I2 -tests [36]. The I2 -test examines the percentage of total
variation across studies, that is due to heterogeneity rather
than chance. A value of I2 greater than about 75% indicates a
high level of heterogeneity.
RESULTS
Thirteen placebo-controlled comparisons have examined
the therapeutic effect of zinc lozenges on the duration of
common cold episodes of natural origin (Table 1 and Fig 1).
The total number of common cold episodes in these trials
was 1407. All the 13 comparisons were double-blind,
although this feature was not a selection criterion. Because
of double-blinding, all trials used allocation concealment.
Weissman et al. [28] used consecutive allocation, but all the
other trials were randomized. All studies examined young
and middle-aged adults, except the Macknin et al. [27] trial,
which examined schoolchildren.
In Table 1, the trials are ordered by the total daily
quantity of elemental zinc obtained from the lozenges. There
is a seven-fold variation in the total daily dose of zinc. There
is also a considerable variation in the results. Seven
comparisons found a statistically significant benefit from
zinc lozenges, but six did not.
Smith et al. [19] did not observe a difference between the
study groups in the duration of colds; however, they did find
a significant reduction in the severity scores on days 4 to 7 of
treatment with P(1-tail)=0.01. Eby et al. [7] did not report
the mean or median duration, but they did report the number
of participants who had no symptoms at the end of the 7-day
trial, an outcome used for calculating the P-value in Table 1.
The duration of colds given in Table 1 for the Eby trial is
based on the exponential model which they used to estimate
the time at which half of their patients were cured.
Table 1 shows that a substantial proportion of the
variation in the results can be explained by the daily zinc
dosage. None of the five comparisons that used less than 75
mg/day of zinc found an effect of zinc lozenges, whereas
seven of the eight comparisons which used over 75 mg/day
of zinc found a statistically significant benefit, although the
benefit in the Smith et al. trial was restricted to the symptom
severity at the late phase of the colds.
The P-values of the individual trials are combined by
using the Fisher method in Table 2. Combining the P-values
of all the 13 comparisons provides very strong evidence that
54 The Open Respiratory Medicine Journal, 2011, Volume 5 Harri Hemilä
the zinc lozenge and placebo groups differ over all the trials.
However, the benefit of zinc is restricted to trials where the
dose was greater than 75 mg/day. A significant effect by zinc
lozenges is seen separately in three high-dose trials where
zinc acetate was used and in five high-dose trials which used
zinc salts other than acetate.
Fig. (1) shows the forest plot of all 13 zinc lozenge
comparisons. There is a highly significant heterogeneity
between the 13 trials on the basis of both the 2 and I2-tests,
with 2(12 df) = 109 and I2 = 89%. The trials are divided into
the low and high dose subgroups as in Table 2 and the two
subgroups are considerably different in their estimate of the
zinc lozenge effect.
In the low-dose trials, there is no evidence of
heterogeneity and all the low-dose comparisons are
consistent with no effect of zinc lozenges. In the eight high-
dose trials, the zinc lozenges reduce the duration of colds by
32% (95% CI: 27% to 37%) but there is strong evidence of
heterogeneity within this high-dose subgroup ( 2(7 df) = 46
and I2 = 85%) (Fig. 1).
Pooling the three high dose (>75 mg/day) zinc acetate
trials gives a mean effect of 42% reduction in the duration of
colds and no heterogeneity is seen between these trials
(Table 3). Five high dose (>75 mg/day) trials used zinc salts
other than acetate [7,19,20,23,24]. None of them reported the
SD value, but SD was estimated from the published survival
curves (Supplementary Material 3) [7,19,23,24] or the
reported t-value [20]. Pooling these five non-acetate trials
gives a mean effect of 20% (95% CI: 12% to 28%) reduction
in the duration of colds. However, there is significant
heterogeneity between these five non-acetate trials
( 2(4 df) = 25.3, P = 0.0001; I2 = 84%).
Sensitivity analysis by the methodological quality of the
trials was not carried out because all trials were double-
blind, which also means that all used concealed allocation.
One trial used consecutive allocation [28], but in a double-
blind trial it is not reasonable to assume that consecutive
Fig. (1). The effect of zinc lozenges on the duration of the common cold. The trials are in the same order as in Table 1, from the highest daily
dose of zinc to the lowest dose. They are divided into the same high dose and low dose subgroups as in Table 2. In the forest plot on the right
side, the vertical line indicates the placebo level. The horizontal line indicates the 95% CI for the effect and the square in the middle of the
horizontal line indicates the point estimate of the effect in the particular trial. Three diamond shapes indicate the pooled effects and their 95%
CI:s for the two subgroups and for all trials. The duration of colds has been transformed to the relative scale so that the duration in the
placebo group is given the value of 100%. Thereby the difference between zinc and placebo groups directly indicates the effect of zinc
lozenges in percentages. See Supplementary Material 2 and Supplementary Material 3 for the extraction of the data and for the calculation of
the relative mean and SD values for the common cold duration.
Zinc Lozenges and the Common Cold The Open Respiratory Medicine Journal, 2011, Volume 5 55
allocation would lead to systematic bias between the study
groups. Furthermore, the trial [28] had low dose of zinc and
therefore its exclusion would strengthen, and not weaken, the
evidence that zinc lozenges differ from the placebo.
All three trials which used zinc acetate in doses higher
than 75 mg/day (Table 3) were methodologically rigorous
randomized trials [21,22,25]. In the Petrus trial, only one
participant was lost from follow-up [22]. In the first Prasad
trial, two participants in the placebo group dropped out on
day 2 [25], whereas there were no drop-outs in the second
Prasad trial [21]. No sensitivity analysis was done in this
subgroup.
There is substantial heterogeneity within the five high-
dose non-acetate trials. Sensitivity analysis was done leaving
out the Eby et al. [7] and Smith et al. [19] trials, which
excluded a large number of randomized participants, 45%
and 36%, respectively. Furthermore, over half of the
common cold durations needed to be imputed to include
these trials in Fig. (1). When these two trials were excluded
from the high-dose non-acetate subgroup, the remaining
three trials lead to 22% (95% CI: 11 to 32%) decrease in the
duration of colds. This confidence interval is essentially the
same as that for all the five non-acetate trials, see above.
Thus, exclusion of these two trials has no influence on
conclusions.
DISCUSSION
Dose-Response Relation Between the Quantity of Zinc
and the Effect on the Common Cold Duration
No effect of zinc lozenges was seen in trials where the
total daily dose of zinc was less than 75 mg, whereas the
majority of trials with higher zinc doses did find benefit
(Tables 1 to 3, Fig. 1). The level of 75 mg per day should not
be considered as an exact biological limit, but as a pragmatic
cut-off point for dichotomizing the trials into low and high
dose trials in these meta-analyses. Nevertheless, the
conclusion that zinc lozenges differ from the placebo does
not depend on the arbitrary cut-off limit because pooling all
the 13 double-blind comparisons also shows that zinc
lozenges differ from the placebo (Table 2 and Fig. 1).
Lozenge Composition and the Level of Free Zinc Ions
In these meta-analyses, the dose-response relation was
examined using the total daily zinc dose as the explanatory
variable. However, this is a simplified approach because
some lozenges contained substances which bind zinc ions
tightly, such as citrate, tartrate or glycine, which decrease the
level of free zinc ions. Thus, even though the same dose of
zinc is used in two different lozenges, other constituents may
lead to substantial differences in the levels of free zinc ions.
Previously, several authors discussed the availability of
zinc ions as a factor that may potentially modify the effect of
zinc lozenges on the common cold [8-15]. Martin assumed
that sucking a zinc-citric acid lozenge would decrease the pH
of saliva to 2.3, pointing out that citrate would not form a
complex with zinc ion at such a low pH level [10]. However,
Zarembo et al. carried out an experiment with 18
participants, finding that sucking a zinc-citric acid lozenge
resulted in saliva pH levels ranging between 3.2 and 5.0
[15]. At such pH levels citrate binds zinc ions as shown by
the published binding curves [10,11,13,14].
The solution chemistry of zinc complexes gives further
understanding of the differences between the zinc trials. Two
research groups, both using lozenges containing 23 mg of
elemental zinc, examined the effect of zinc lozenges on
experimentally induced rhinovirus colds. Al-Nakib et al.
[37,38] found a significant benefit using the lozenges,
whereas Farr et al. found none [39]. However, Farr’s lozenge
contained 2% citric acid whereas Al-Nakib’s lozenge did not,
a difference in lozenge composition which could explain the
divergent results [11-14].
Among the trials with natural common cold episodes in
Table 1, Godfrey et al. [20] administered a high dose of zinc,
but glycine in the lozenge bound 80% of the zinc ions to
complexes [11-14], which could explain the rather small
benefit compared with the other trials which used high doses
of zinc (Table 1). Turner et al. found no effect using 69
mg/day of zinc acetate [23]. However, Eby pointed out that
Turner’s lozenges contained palm kernel and cotton seed
oils, and at the high temperature used in the manufacture of
the lozenges, these ingredients react with zinc ions making
insoluble compounds [40]. The lozenge used by Douglas
et al. [26] contained tartaric acid, which binds zinc [11,13,14].
Although the solution chemistry of zinc ions may offer
more detailed explanations of the variation between the trial
results, the power of the dose-response analysis can be seen
even by counting the total daily dosage of elemental zinc
obtained from the lozenges (Tables 1 and 2; Fig. 1).
Table 3. Pooling the Results of the High Dose Zinc Acetate Trials
Intervention
Zinc Placebo
Trial
No. of Colds
Mean Duration
of Colds (Days)
SD No. of Colds
Mean Duration
of Colds (Days)
SD
Effect of Zinc Acetate on Common Cold Duration
a
(95% CI)
Petrus et al. 1998 [22]b 52 3.80 1.63 49 5.10 2.96 -26% (-44%, -7%)
Prasad et al. 2000 [25] 25 4.5 1.6 23 8.1 1.8 -44% (-56%, -33%)
Prasad et al. 2008 [21] 25 4.00 1.04 25 7.12 1.26 -44% (-53%, -35%)
Pooled results 102 97 -42% (-48%, -35%)
aThere is no evidence of heterogeneity over these three trials: 2(2 df) = 3.5 (P = 0.2), I2 = 43%. Calculations were done by using the RevMan program [35].
bPetrus et al. [22] reported the results inaccurately to only one decimal place, giving 3.8 and 5.1 for the mean duration of colds and 0.2 and 0.4 for the SE of the mean in the zinc and
placebo groups, respectively. These more accurate figures were kindly provided by Ken Lawson (March 4, 2009).
56 The Open Respiratory Medicine Journal, 2011, Volume 5 Harri Hemilä
Safety of Zinc
In several common cold trials, the zinc lozenges caused
acute adverse effects, such as bad taste and constipation, but
none of the trials reported long term harm. Furthermore,
several of the reported adverse effects, in particular on taste,
may have been caused by the specific lozenge composition,
and may not reflect the effects of zinc ions per se [13]. In the
most recent trial on zinc acetate, there were no significant
differences between the zinc and placebo groups in the
occurrence of adverse effects although the daily dose was 92
mg [21].
For certain patients, zinc has been administered at high
doses, 150 mg/day, for therapeutic purposes for months or
years [41-45]. Deficiency of copper has been reported as a
consequence of long-term zinc supplementation [44,45], but
a six-week experiment did not find any effect from 150
mg/day of zinc on plasma copper levels [46]. On the basis of
these long-term studies with high zinc doses, there does not
seem to be any basis for assuming that treating the common
cold for a week with high doses of zinc in the form of
lozenges would cause unanticipated harm. A patient
suffering from acute adverse effects such as bad taste can
simply stop taking the lozenges.
Implications for Further Research
Table 1 suggests that the benefit of zinc lozenges perhaps
can be obtained with doses substantially lower than Eby et al.
used in the first trial on the topic [7]. Four trials used 80 to
92 mg of zinc per day and observed significant benefit
(Table 1). Three of them used lozenges containing zinc
acetate (Table 3), which does not form complexes with zinc
ions [13,14]. Obviously, new trials should be carried out to
confirm the benefit of zinc acetate lozenges at a dosage of
about 80 mg per day, and to examine whether even lower
daily doses in appropriately formulated lozenges might be
effective.
Other Reviews on the Effect of Zinc Lozenges on the
Common Cold
Two groups of reviewers concluded that there is no
evidence that zinc lozenges are beneficial against colds.
Jackson et al. [47,48] found statistically significant
heterogeneity between the zinc trials. They calculated a
pooled estimate of effect, although the evidence of
heterogeneity seriously challenges the validity of any single
overall estimate. Faced with heterogeneous results, the main
focus of the reviewers should be on trying to understand the
sources of the heterogeneity [49]. Although Jackson
suggested that some of the negative results might be
explained by low zinc ion availability, they did not examine
the …