“Zinc gluconate in the form and dosage studied significantly reduced the duration of symptoms of the common cold.” Mossad et al., "Zinc Gluconate Lozenges for Treating the Common A Randomized, Double-Blind, Placebo-Controlled Study." Annals of Internal Medicine Vol. 125, No. 2 (July 15, 1996): Page 81. Print.

1. Reprinted from ANNALS OF INTERNAL MEDICINE Vol.125;No.2, 15 July 1996
Printedin U.S.A.
15July 1996 Votume 125 Number 2
Annalsof InternalMedicine
Zinc Gluconate Lozengesfor Treating the Common Cold
A Randomized,Double-Blind, Placebo-ControlledStudy
Sherif B. Mossad,MD; Michael L. Macknin, MD; Sharon V. Medendorp, MPH;
and PamelaMason, BSN, MBA
Background: The common cold is one of the most fre- P < 0.001),nausea(20% compared with 4%; P "" 0.02), and
quent human illnessesand is responsible for substantial bad-taste reactions (SO%compared with 30%; P < 0.001).
morbidity and economic loss. No consistently effective Conclusion: Zinc gluconate in the form and dosagestud-
therapy for the common cold has been well documented, ied significantly reduced the duration of symptomsof the
but evidence suggeststhat several possible mechanisms common cold. The mechanism of action of this substance
may make zinc an effective treatment. in treating the common cold remains unknown. Individual
Objectl".: To test the efficacy of zinc gluconate lozenges patients must decide whether the possible beneficial ef-
in reducing the duration of symptoms causedby the com- fects of zinc gluconate on cold symptoms outweigh the
mon cold. possibleadverseeffects.
Design: Randomized, double-blind, placebo-controlled AM Inlml M«l. 1996;12S:81-88.
study. From the OevelandOinic Foundation,aeveland, Ohio. For
Setting: Outpatientdepartmentof a largetertiary care current author addresses, see end of text.
center.
The common cold is one of the most frequently
Patients: 100 employeesof the Cleveland Clinic who de-
.1. occurring human illnesses in the world. More
veloped symptoms of the common cold within 24 hours
than 200 viruses can cause common colds in adults,
before enrollment.
including rhinoviruses (the most frequent cause),
Intervention: Patients in the zinc group (n - SO) received coronaviruses,adenoviruses,respiratory syncytial vi-
lozenges (one lozenge every 2 hours while awake) con- rus, and parainfluenza viruses. In the United States
taining 13.3mg of zinc from zinc gluconate as long asthey each year, adults develop an averageof two to four
had cold symptoms. Patients in the placebo group (n - SO) colds and children develop an average of six to
received similarly administered lozenges that contained eight colds (1, 2). The morbidity resulting from this
5% calcium lactate penta hydrate instead of zinc glu-
diseaseand the subsequentfinancial loss in terms of
conate.
working hours are substantial (3). Many previously
M.in Outcome MHsures: Subjective daily symptom described treatments have not provided consistent
scores cough, headache,hoarseness,
for muscleache,nasal or well-documented relief of symptoms. Even a
drainage, nasal congestion, scratchy throat. sore throat, treatment that is only partially effective in relieving
sneezing,and fever (assessed oral temperature).
by cold symptomscould markedly reduce physical mal-
Results: The time to complete resolution of symptoms aise and economic lossesin a large population.
was significantly shorter in the zinc group than in the The medical literature describes many possible
placebo group (median, 4.4 days compared with 7.6 days; mechanismsby which zinc may treat the common
P < 0.001). The zinc group had significantly fewer days cold, and seven controlled trials have studied the
with coughing (median, 2.0 days compared with 4.5 days; use of zinc for this purpose. All sevenwere double-
P = 0.04), headache (2.0 days and 3.0 days; P = 0.02),
blind, placebo-controlled studies, but each used dif-
hoarseness daysand 3.0 days; P = 0.02), nasal conges-
(2.0 ferent formulations and dosagesof zinc. Three of
tion (4.0 daysand 6.0 days;P = 0.002), nasal drainage (4.0
daysand 7.0 days;P < 0.001),and sore throat (1.0 day and
3.0 days;P < 0.001).The groups did not differ significantly
in the resolution of fever, muscleache, scratchythroat, or
sneezing. More patients in the zinc group than In the
placebo group had side effects (90% compared with 62%;

2. thesestudiesshowedthat zinc had a beneficialef::-
these studies showed that zinc had a beneficial ef::- the studyas specified the protocolwere enrolled
by
feet (4-6) and four did not (7-10). In the studies'
fect (4-6) and four did not (7-10). In the studies in a ramefor one of two prizes:dinner for two or
that examined
that examinedvirus shedding 7), zinc treatment
virus shedding (5, 7), zinc treatment
(5, a trip for two to the Bahamas. The Institutional
had no elect on this shedding.
had no elect on this shedding. ReviewBoard at the aeveland ainic Foundation
We designed studysimilar to that of Godfrey
We designeda study similar to that of Godfrey
a approved study,and participants
the gaveinformed
and colleagues and used the symptomscore
and colleagues (6) and used the symptom score
(6) consent the time of enrollment.Participants
at were
developedby these researchers.
developed by these researchers. We emphasized
We emphasized informed of the placebo-controlled, double-blind
startingtreatment
starting treatment within 24 hoursafter the onsetof
within 24 hours after the onset of natureof the study.
symptoms,
symptoms,because
because Godfrey and colleagues
Godfrey and colleagues found
found Patients who volunteered the studywere en-
for
that early treatmentwas most elective. We used
that early treatment was most elective. We used rolled only if they had had cold symptoms 24 for
zinc gluconate
zinc gluconate lozenges,
lozenges,which appeared be well
which appeared to be well
to hoursor less.Patients musthavehad at leasttwo of
toleratedand had the best bioavailability
tolerated and had the best bioavailability profile in
profile in the following10 symptoms: cough,headache, hoarse-
previousstudies.Other studies(4-7, 9) used loz-
previous studies. Other studies (4-7, 9) used loz- ness,muscleache,nasaldrainage, nasalcongestion,
engescontaining 23 mg of zinc. To improvepalat-
engescontaining23 mg of zinc. To improve palat- scratchy throat,sorethroat,sneezing, an oral tem-
or
ability, lozenges our studycontained13.3mg of
ability, lozengesin our study contained 13.3 mg of
in perature greater than 37.7°c. Patientswere ex-
zinc. This provided a local concentrationof zinc
zinc. This provided a local concentration of zinc cludedif theywere pregnant, had a knownimmune
ions of about4.4 mmo1/L, amountgreaterthan
ions of about 4.4 mmoVL, an amount greater than
an deficiency, had had symptoms the common
or of
that necessary suppress
that necessaryto suppressrhinovirus(0.1 mmoVL)
to rhinovirus (0.1 mmol/L) cold for more than 24 hours.
(11, 12).The placebo
(11, 12). The placebo lozenge
lozengecontained calcium
contained 5% calcium
5% The zinc gluconate-glycine placebo
and lozenges
lactateso that it had a medicinaltaste similar to
lactate so that it had a medicinal taste similar to were supplied by the Quigley Corporation of
that of the zinc gluconatelozenge.
that of the zinc gluconate lozenge. Doylestown, Pennsylvania. zinc lozenges
The con-
Ours was a pragmaticstudy designedto deter-
Ours was a pragmatic study designed to deter- sistedof a boiled hard-candy base preparedwith
mine the efficacyof zinc gluconatelozenges re-
mine the efficacy of zinc gluconate lozengesin re-
in approximatelyequal proportions of sucroseand
Jcing clinical symptomscores under conditions
lcing clinical symptom scores under conditions com syrup,zinc gluconatetrihydrate (AKZO Che-
'1t reflectedusual medicalcare for the common
"it reflected usual medical care for the common mie, Amersfoort,the Netherlands), molar propor-
a
cold (13, 14).We did not seekto define the mech-
cold (13, 14). We did not seek to define the mech- tion of glycine(aminoacetic acid), and lemon and
anismof any zinc elect. Althoughvirus culturesor
anism of any zinc elect. Although virus cultures or lime flavoring oils. The mixture was formed into
serologictests might have been desirable,we de-
serologic tests might have been desirable, we de- lozenges weighed4.4 g and contained13.3mg
that
cidednot to do thesetestsbecause
cided not to do these tests becausethey are almost
they are almost of zinc. Placebo lozenges, weighing4.4 g, were
also
neverdonein the courseof standardcare.
never done in the course of standard care. preparedfrom the sameflavoredhard-candy base
and contained5.0% calcium lactate pentahydrate.
Placebo and active lozengeswere identical in
weight,appearance, flavoringcontent,and texture.
Methods
Methods The zinc lozenges, however,were more astringent
. than the placebo lozenges.
StudyDesign A statisticalconsultant prepared computer-gen-
a
We determined that a 50% reductionin the du- erated randomizationcode and the packages of
ration of symptoms(in days) would representa medication. The packages were identicalin appear-
significantclinical elect. A previousstudy of zinc ance exceptfor the randomizationnumbers.The
gluconate given during the first day of cold symp- studymedication distnDuted the studynurse,
was by
tomssuggested the duration of illnesswas re-
that who wasmasked treatmentassignments.
to Patients
ducedfrom approximately days to 4 daysafter
8 weregiven 120lozenges were askedto dissolve
and
treatmentbegan(6). Our previousresearch pa- on 1 lozenge their mouthsevery2 hourswhile awake
in
tients with colds who were seen at the Oeveland for as long as they had cold symptoms. The study
Clinic suggested the mean ~uration(:tSD) of
that nurseadministered first lozenge assess
the to initial
cold symptoms was approximately :t 6 days (15,
7 tolerability.Participantswereasked takeno other
to
16).We chosea sample sizeof 100patientsso that cold preparationsduring the study period. Acet-
we coulddetecta dilerence in the meannumberof aminophen samplesand oral digital thermometers
daysof symptoms from 8 daysin the placebo group weregivento the patientsat the time of enrollment.
to 4 daysin the zinc group with a standarddevia- All patientswere calledon the second of med-
day
tion of 6 days,a two-sided value of 0.05,and an
P ication useto makesure that they were not devel-
approximate powerof 90%. oping a more seriousillnessand to assess ade-
the
Patientswere recruited from amongthe Cleve- quacy of the masking through responses a to
land ainic staft'throughannouncements internal
in questionnaire. assessing adequacy the pla-
By the of
Oinic publications by word of mouth.One hun-
and cebo on the secondday of treatmentrather than
dred volunteers were enrolled between3 October only at the end of treatment, hopedto decrease
we
and 4 November 1994.All patientswho completed the likelihoodthat a rapid curewould help patients
82 .
15July 1996 An1Ul1s InlenuUMediciM
of . Volume 125 . Number2

3. in the zinc group correctly determine that they were '_b'. 1. DemographicCharacteristics 99 Volunteers
of
ReceivingZinc or PlaceboLozenges
for
receiving the active medication. This questionnaire Treatmentof the CommonCold
was also administered at the end of treatment with
the addition of questions about the occurrence of
specific, previously described side elects of zinc
therapy.
Patients returned to the ainic for the final visit
".1
M81~SD 37.5 :t 1.5
MedlIn (minlmum-mlXimum) 36.1 (22.3-54.6)
within 1 day of noting that their cold symptomshad Sex.n~
resolved. At this visit, they returned unused loz- Men
enges so that adherence to the protocol could be women
RIce. ~
n
checked through lozenge counts, and the study White
nurse confirmed that cold symptoms had resolved. Blick
Other
Patients were asked to complete a daily log doc- ~
Smokers. n /%)
umenting the severity of symptoms and the medica- PMients with iIIefgies. n ttW
tions taken throughout the duration of their cold
for as long as 18 days. Every day, patients graded
each symptom as 0 for none, 1 for mild, 2 for
moderate, or 3 for severe. Total symptom scores
)tom four or more lozengesper day for the first 4 daysof
were calculated by summing the scores of the 10
s the study (16 lozenges) and if they took no antibi-
symptomsfor each day. Cold resolution was defined otic agents.
as resolution of all symptoms (a total symptom
iii
score of 0) or resolution of all but one mild symp-
tom (a total symptom score of 1). Results
Statistical Analysis One hundred patients were enrolled in the study;
The time to cold resolution was calculated as the
llated SOwere assigned to the zinc group, and SOwere
number of days from study entry. Resolution rates
Ilution assigned to the placebo group. All patients were
were estimated using the Kaplan-Meier method,
ier Oeveland Clinic employees older than 18 years of
and resolution profiles were compared between
~d age. One patient in the zinc group withdrew from
groups using the log-rank test (17, 18). We esti-
:). the study on the first day because she could not
mated median resolution times using the method tolerate the lozenges; she did not complete the
suggestedby Lee (19). The elect of treatment on
'eatment symptom diary. All other patients, as directly ob-
individual symptoms was examined by comparing served by the study nurse, indicated that they had
the number of days with each symptom using the
n good tolerance of the first lozenge. Demographic
Wilcoxon rank-sum test. For analysis of treatment
If characteristicsof the groups are given in Table 1.
effect, we combined hoarseness,sore throat, and The mean (~ SD) and median symptom scoresat
scratchythroat into a category called "throat symp-
hroat baseline (the first measurement)were 8.6 ~ 3.3 and
toms" and nasal drainage and congestion into a
tion 8 for the entire sample, 9.3:t 3.6 and 8 for the
category called "nasal symptoms." Plots i of individ- placebo group, and 7.9 ~ 2.8 and 8 for the zinc
ual patient symptoms give the percentage of the
tage group. In practice, an increase in score from 8 to 9
baselinetotal severity score (sum of symptom scores
ptom entails scoring one symptom one grade higher or
for all patients) by assignmentgroup and study day.
:I developing another mild symptom. Six hours after
When appropriate, we used the Fisher exact test
r the study began, the mean symptom scores for the
and the chi-square test to analyze associationsbe-
ciations placebo group (9.3 ~ 4.2; median, 9) and the zinc
tween the side effects and assignedgroups. Patient
LIpS. group (8.7 ~ 4.0; median, 8) were closer.
adherence was examined by cOmparing the total
g The incidence of individual symptomsat baseline
lozenge counts between the two groups using the
s was similar in the two groups for all but two symp-
Wilcoxon rank-sum test. toms: sneezing (31 of SO placebo recipients [62%]
ntention-to-
These analyseswere done using an intention-to- and 38 of 49 zinc recipients [77.5%]; P = 0.09) and
treat framework, regardless of patient adherence sore throat (39 of SOplacebo recipients [78%] and
(20-22). Before the randomization code was bro-
Ie was bro- 2S of 49 zinc recipients [51%]; P = 0.005). No pa-
ken, patients who received antibiotic therapy or tients had fever at baseline.
whosecondition was diagnosedby a physicianas an
sician Eight patients (six in the placebo group and two
illnessother than the common cold were considered in the zinc group) had colds that did not resolve
nonadherent. Patients who wrote their diaries from
liaries while they remained in the study. Two of these
memory were also considerednonadherent. Patients
:nt. patients (both were placebo recipients) completed
wereconsidered adherent they took an averageof
if I average the 18 daysof the study, and the remaining six (four
.
15 July 1996 AnM/sof Intunlll Medicine. Volume125. Number
2 83

4. signrnent (P > 0.2). Even when the 17 nonadherent
. patients were excluded, symptoms in the zinc group
l still resolved significantly faster according to both
definitions of symptom resolution (P < 0.001). The
median duration of symptoms for the adherent pa-
I tients in the placebo and zinc groups was 7.2 and
i 3.9 days, respectively, for complete resolution and
t 5.7 and 3.4 days, respectively, for near-complete
resolution.
J Figures 2 and 3 show the percentageof the orig-
inal symptom score (each day by group assignment)
for nasal symptoms and throat symptoms.The zinc
group had significantly fewer days with any symp-
tom, nasal symptoms, throat symptoms, coughing,
headache,hoarseness, nasal congestion,nasal drain-
age,and sore throat. The groups did not differ signif-
were placebo recipients and two were zinc recipi- icantly in the resolution of muscle ache, scratchy
ents) dropped out after 7 to 16 days. In addition, throat, sneezing, fever (Table 2).
or
one patient recorded his symptoms for 18 days but We calculated the total number of lozengesfrom
indicated that his cold resolved on day 19. counts of returned lozenges and from patient dia-
We used the Kaplan-Meier method to estimate ries. When we found discrepancies,we used actual
the percentage of patients whose colds completely lozengecounts. During the entire study, the placebo
rf"solved(Figure 1) and almost completely resolved group took a mean of 49 :t 30 lozenges(median, 42
"n each day of the study. The median time to lozenges) and the zinc group took a mean of
rt:solution of all symptoms was 7.6 days in the pla- 36:t 22 lozenges(median, 28 lozenges)(P = 0.03).
cebo group and 4.4 days in the zinc group; the The placebo group took an average of 5 :t 2 loz-
median time to resolution of all but one mild symp- enges per day (median, 5 lozenges per day),
tom (data not shown) was 7.5 days in the placebo whereas the zinc group took an average of 6 :t 2
group and 3.7 days in the zinc group. The results of lozengesper day (median, 5 lozengesper day) (P =
the log-rank test and the plot of these distributions 0.20). Becausetheir colds lasted longer, the placebo
indicate that symptoms resolved significantly faster group used significantly more lozengesthan the zinc
in the zinc group than in the placebo group (P < group, but the number of lozengesper day of symp-
0.001). This effect was also seen when the end of toms did not differ between the two groups.
the cold was defined as almost complete resolution Use of acetaminophen not differ significantly
> did
(P < 0.001). The study nurse directly observed betweenthe two groups (P = 0.10); the placebo
whether the patients who returned their study forms group took a median of 6 acetaminophen tablets,
and unused medication within 1 day of reported and the zinc group took a median of 4 tablets.
resolution of symptomswere free of symptoms. Despite instructions to the contrary, 15 patients (10
Seventeenof the 100 patients (10 in the zinc placebo recipients and 5 zinc recipients) took other
group and 7 in the placebo group) were considered cold medications during the study (P = 0.17).
nonadherent.Of these 17, 6 (2 zinc recipients, 1 of
whom also took antibiotic agents, and 4 placebo
recipients) did not take enough medication for rea-
sons that were not stated; 5 (all zinc recipients)
stopped taking the lozengesbecauseof adverse ef-
fects (bad taste in 3 patients, sore mouth in 1 pa-
tient, and a "lump in back of throat" in 1 patient);
4 (2 zinc recipients, 1 of whom also could not
tolerate the taste of the medicine, and 2 placebo
recipients) took antibiotic agents; 2 (both zinc re-
cipients) reconstructed their diaries from memory;
and 2 (1 zinc recipient and 1 placebo recipient)
stopped keeping a record for reasonsthat were not
stated. When data were analyzed after these 17
nonadherentpatients were excluded, the study con-
clusions remained the same. No significant relation:
was seen between adherence status and group as- ~
84 .
IS July 1996 A1IIUIU of Inlmull Medicine. Volume 125 Number2

5. cipients (16%) and 12 zinc recipients (25%) re-
- . ported that the lozenges tasted sour; 6 placebo
(12%) and 20 zinc (41%) recipients reported a bit-
ter taste; and 4 placebo (8%) and 4 zinc (8%)
recipients reported a salty taste. Many patients re-
ported that the lozenges had an aftertaste. Thirty-
four of 50 placebo recipients (68%) and 6 of 49 zinc
recipients (12%) reported no aftertaste (P < 0.001).
Twelve placebo recipients (24%) and 22 zinc recip-
"0.. ients (45%) reported a mild aftertaste;2 placebo
u"o.. (4%) and 17zinc (35%) recipientsreporteda mod-
, , , :..;..~ erate aftertaste; and 1 placebo recipient (2%) and 3
3 .'5'5,715 zinc (6%) recipients reported a severe aftertaste.
Two patients (1 in the placebo group and 1 in the
Figure J. Percent8ge origin_I thl'Ollt symptoms,:- :::. d8y
of - 88dI ~ zinc group) did not answer the question.
by trutment group. Throat symptomswere hoal'Seness. throat. and
sore
cebo group.
scratchythroat. Solid hne = zinc group; dotted line = placebo group. We ascertained side effects in two ways. During
the study, we asked patients to list all of the side
effects of their medication. This open-ended ques-
Questions to evaluate the efficacy of masking to tion was the only one asked during the study period.
group assignmentwere asked after the first day of Seventeen of 49 zinc recipients reported that no
treatment and at the end of the study. Patientswere
atients side effects developed with their medication before
asked to guesstheir assignmentfrom among seven
mong the conclusion of the study. In these patients, the
cebo, possi-
choices: certainly placebo, probably placebo, mean (4.7) and median (4.0) numbers of days until
bly placebo, do not know, certainly active, probably
ve, only one mild symptom remained was the same as
active, or possibly active. By assigning all guesses
aU the Dumber in the 32 patients with identified side
that mentioned "placebo" as placebo and all
)() aU effects. The zinc recipients with and without identi-
guesses that mentioned "active" as zinc, the follow-
, fled side effects also had a similar mean (5.1 days
ing results were obtained. On the initial question-
al and 5.5 days, respectively) and median (4.5 daysand
naire, 50% of the placebo recipients (25 of SO)and
i 50) 6.0 days, respectively) time until symptoms com-
55.2% of the zinc recipients (27 of 49) correctly
9) pletely resolved (P > 0.2).
guessedtheir study assignment.At the end of the The second method used to determine side ef-
study, 54% of the placebo recipients (27 of SO)aDd
r 50) and fects entailed listing all of the common side effects
53.1 of the zinc recipients (20 of 49) correctly
% 9) of zinc and asking patients at the end of the study
guessed their treatment assignment.Sixty-five of the
y-five whether these or other side effects developed while
99 patients (65.7%) maintained their original guess
'iginal they were taking the study medication (Table 3). As
at the end of the study. Becauseno clear pattern of
Ir expected, patients described more side effects in
movement of guesses was seen between the groups,
masking appears to have been maintained during
ined
the study. T8bIe2. Duration individual
of Symptoms the
of
After the first day of treatment, 46% of the pla-
, of the pla- Common Cold
cebo recipients and 59% of the zinc recipients said
;ipieDts
I . h. Symptom Duration in Duration
in PVIIue*
that the study medication had helped alleviate t elr
evlate their Placebo
Group Zinc
Group
symptoms(P = 0.19). At the end of the study, 44%
study, 44% (n- SO) (n - 49)
of the placebo recipients and 59% of the zinc re-
the zinc re- dt
cipients said that the study medication had helped
had helped
improve the cold symptoms (P =
0.13).When the
. When the
d . h
NISIIsyrnptOmS*
ThroItsymptoms§
7.0(4. 13)
4.0 (3.9)
4.0(3.~
3.0(t, 5)
<0.001
0.004
zinc and placebo groups were subdivided IOto t e
e into the Cough 4.5(1.10) 2.0(1.~ 0.04
seven subgroups on the basis of how certain the
certain th
the HNdKhe 3.0(1.5) 2.0(0.3) 0.02
HoIrseness 3.0 (0. 8) 2.0 to. 3) 0.G2
patients were about their group assignmenton the
Rent on e NISII
congtStion 6.0(3.12) 4.0(2,6) 0.002
first day of treatment, the mean and median dura-
edian dura- ~ draiNgl 7.0(4.II) 4.0(2.5) <0.001
Iw Sorethroat 3.0(1. 6) 1.0(0. 3) <O.OCI1
tions of symptoms in the zinc group were a ays
were always Muscleache 2.0 (1, 5) 1.0(0. 3) 0.11
shorter than those in the placebo group. ). Saatchythrolt 3.0(1,5) 3.00,4) 0.17
(76%) d Sneezing 3.0(1,5) 2.0(1,.t) 0.20
Thirty-eight of 50 placebo recipients (76%) an and fMr 0 (0.0) 0 to.O) G.15t
28 of 49 zinc recipients (57%) describedthe taste of
the lozengesas sweet. Patients were also as
ked t
so asked to 0
.v-- ..
t
WIIaJIIan
rri-
upmsed
IIeSl
.. tht mediIn125m,15mpttCtntiles).
chooseother tastesthat applied to their medication ,
medication, ,
. ~
-nwo.t~
-- nasal
-- ~ dr.,. 8IIdnasal scrM(hy IhroIt
S(Q
~
IIvoaI. 8IId
including sour, bitter, and salty. Eight placebo re-
placebo re- , IIy FtWr -
ttw euct
. Medicine Volume 125 Number
IS July 1996 AnMls of /1IlemaJ 2 . . 85
85

6. .-- iI. .>'U'" ""...~ n...pun... UJ ~ YUIUn_n ~"'IiI preVIous studJes that showed a beneficial effect of
T8bI. 3. Sideor Placebo I.ozenges 99 Volunteen Receiving
Zinc
EffectsReportedby for Trutment of the - .. t: .
Zincor PlaceboLozenges Treatment of the -
for
h
Id
'
Common
Cold.
.
usmg
zmc
lor
treatIDg
t
e
common
co
,
partlCU
I
ar
I
y
CommonColde when zinc is started within the first 24 hours of
Variable PIIcebo Group ZIncGroup onset of symptoms.Of the four studies that did not
Variable Placebo
In.. Group
50) ZIncGroup
In.. 49) show a beneficial effect, three (7-9) were criticized
(II .. 50) In .. 49)
n'" for using a lozenge formulation that inactivated the
ntIW
zinc (24-26) and one (10) used a possiblyineffective
-
CI' 0.O2)t
" .. 0.O2)t
2 (4.CJt
2 (44
10(20.4)
10(20.4)
dose of 4.5 mg of zinc per lozenge. Of the three
VomIting
=:'PIin I 12,
~g:0) 0
~(&.1) studies that did show a beneficial effect, one (4)
AbdomNI PIin
DiaIThN . 1 (2.0)
2(4.0) 3 (&.1)
2(4.1) reported a strong treatment effect (P < 0.001)at 7
DiIntI8I 2(4.0) 2«'.1)
Constipation
~(P>0.2)t (P> 0.2>* 0
Ig(20.01 1 12.0)
,~g:>.5) days (14% of zinc recipients compared with 54% of
Mouthirritation
Bad.tIste 0.001>*
(P 0.0011*
< 10(20.0)
15 (30.0) 1212..5)
39(79.6) placebo recipients had symptomsat 7 days) but also
e.d tIstt (P< 15(30.0) 39 (79.6)
Dizziness
=:e 0
g 0
g noted a high rate of side effects in the zinc group.
HeiIdache 0 0
Dlymou1h 6(12.0) 6(12.2) This finding caused some investigators to question
DrymouIt1
Other > 0.2)"
CI' 6 (12.0)
2 (4.0)
Numberofsideefects(p<O.OOI)"2 (..0)
Other > 0.2)"
(P
6 (12.2)
5 (10.2)
5 (10.2) t he vaIIdity 0f t he mas ng and therelore the valId
'
lei t: ' -
Number of Side efects (P < 0.001)e
0 19 (38.0) 5 (10.2) ity of the study results (27). AI-Nakib and coi-
0
l 26(38.0)
19 (52.0) 19(10.2)
5
2
1 2 (4.0)
26 (52.0) 17(38.8)
(34.7)
19(38.8) .
Ieagues (5) used ZinC gluconate Iozenges In persons
.
2
3 2 (4.0)
3 (6.0) 17(304.7)
8 (16.3) with experimentally induced colds and found no
3
" St8IIcIII8Sting
. StIMaI tilling -
t ., the FiIIw 8IId ..
- done
when
3(6.0)
01
done when adequIW numb8n 01 ~
t ... II» fisher 8IIICt lISt.
8(16.3)
aqu,te numb8n pIIiInIs"PO'I8d tIects.
IIdI
/IIIOftId licit Ifects.
benefit
note a
in giving
reduction
zinc prophylactically,
in mean daily clinical
but they did
scores com-
..,thecN1quft-.
""II»~_. d .h . I bo ..
pare WIt scores In p ace recipients on days 4
(P < 0.01) and 5 (P < 0.05) of treatment. The treat-
response to this question than in response to the ment was well tolerated, and the placebo lozenge
response to this question than in response to the
open-ended question alone. Patients in the zinc was not distinguished from the zinc lozengeby taste
open-ended question alone. Patients in the zinc
group reported more side effects per person (25 or appearance.
group reported more side effects per person (25
zinc recipients and 5 placebo recipients had two or Godfrey and colleagues (6) compared a nonche-
zinc recipients and 5 placebo recipients had two or
more side effects; P < 0.001), significantly more
more side effects; P < 0.001), significantly more lating formulation, zinc gluconate-glycine, which re-
nausea (10 patients compared with 2 patients;
2
nausea (10 patients compared with (39patients; leases93% of contained zinc in saliva, with a pia-
P = 0.02), and more bad-taste reactions (39 patients
P = 0.02), and more bad-taste reactions patients cebo containing highly astringent tannic acid and
compared with 15 patients; P < 0.001). The other
with 15 patients; P < 0.001), The other saccharin. They reported a 26% reduction in the
compared
symptomsdescribed(vomiting, abdominal pain, diar-
symptomsdescribed(vomiting, abdominal pain, diar- duration of colds when treatment was begun during
rhea, constipation, mouth irritation, and dry mouth) the second day of symptoms and a 42% reduction
rhea, constipation, mouth irritation, and dry mouth)
did not differ significantly between the two groups,
did not differ significantly between the two groups. (from 9.1 days to 5.3 days) when treatment was
begun on the first day of symptoms.Our study was
similar to that of Godfrey and colleagues;we used
Discussion the same symptom score, emphasizedstarting treat-
Discussion
ment within 24 hours after onset of symptoms,and
The common cold still has no definitive cure. At used a reduced dose of zinc to improve the palat-
best, available over-the-counter medications mini- ability of the lozenge.
mally alleviate cold symptoms (23). Our study The mechanismsthrough which zinc affects the
showed that the time to resolution of all symptoms common cold remain to be determined, but several
was significantly shorter in the zinc group. The zinc possibilities have been described. Zinc prevents the
group had significantly fewer days with coughing, formation of viral capsid proteins, thereby inhibiting
headache,hoarseness, nasal congestion,nasal drain- in vitro replication of several viruses, including rhi-
age,and sore throat but had more patients with side novirus (11, 12, 28-30). Zinc combines with the
effects. The fact that zinc recipients and placebo carboxyl termini (negatively charged canyons) of
recipients did not differ significantly in their subjec- rhinovirus coat proteins, which may prevent the vi-
live overall impression of whether the study medi- rus from combining with the tissue-surfaceprotein
cation had helped alleviate their cold symptoms is (intracellular adhesion molecule type 1) and enter-
somewhatsurprising. However, global assessment by iog the cell. This processstops further reproduction
patients may be based largely on subjective esti- (31, 32), Extracellular zinc may exert antiviral ef-
mates of how long a cold "should" last rather than fects by stabilizing and protecting cell membranes
on objective knowledge of the duration; this created by uncertain means (30, 33-36). In vitro studies
much variation in subjective estimates of whether have suggestedthat zinc may induce production of
the actual duration of the patients' cold symptoms interferon (37), Zinc ions also have human prosta-
were or were not "improved" with either treatment. glandin metabolite-inhibiting properties at 0.01 to
The results of our study are similar to those of 0.1 mmol (38), which may also account for the
86 .
15July 1996 Annals of InlmuJl MediciM . Volume 125 . Number2

7. ability of zinc to help relievesymptoms the com- - fects in the dosesused in our study.Thus, we do
of
mon cold. not believethat our resultsreflectan adverse
effect
Our study has some limitations. First,, we did not
we did not of the placebo administration.
the
establisha microbiological diagnosisof the common In our study, the only statistically significant ad-
ective infor-
cold. We relied solely on patients' subjective infor- verse effects of zinc therapy were bad taste and
study nurse.
mation and clinical evaluation by the study nurse. nausea.Although the incidence of mouth irritation
We elected not to do microbiological studies of
I studies did not differ significantly between the two groups,
rhinovirus because the expense of such studies is
:h is mouth irritation may still be a clinically significant
prohibitive, and our goal was only to ) determine
determine adverse effect because the placebo may also have
whether zinc helped to relieve cold symptoms.The
lpt~ms. The been irritating. We assessed possibility that pa-
the
he inftuenza
fact that the study was done early in the influenza tients withdrew from the study becauseof side ef-
ad
season,when no cases of influenza had been re- re- fects before their colds had completely resolved.We
~rts
ported at the Oeveland Oinic, supports the as- as- hypothesized that patients who recognized side ef-
ave ~comf-
sumption that most of our patients did have a com- fects of medication before the end of the study may
mon cold. Doing the study at a di1ferent time of
'ent time 0 h d .d d ' I th I d d' .
f . ave ecl e to VlOate e protoco an IscontIDue
~
year could have involved di1ferent types of viruses,
0 VIrUSeS
b ' their medications before they were completely well,
which might have altered the results. The absence
(lie a sence . h . .
II
(beca
f
h
.
of fever at baseline in all patients suggests that
ts
th
t
elt
er
IDtentlona
y
use
0
t
e
perceIVe
d
uD-
~~~
certain viruses,such as influenza, parainfluenza,and
anad pleasantnessof the side effects) or unintentionally
.mon ~Id in (because the side effects masked their cold symp-
adenovirus,were unlikely causesof common cold in
~ patients in
our patients. Second,the fact that more patients in toms). No statistically significant association was
up had sore
the zinc group than in the placebo group had sore seen between the presence or absenceof medica-
different vi-
throats at baseline could suggest that di1ferent vi- tion side effects recognizedbefore the conclusion of
ruseswere responsiblefor common cold in the two
:I in the two the study and the duration of the patients' illnesses.
ished within
groups. This difference, however, diminished within This is further evidencethat patients adhered to the
we assessed
the first 12 hours of the study. Third, we assessed protocol and did not prematurely stop taking their
t by review-
compliance with the assignedtreatment by review- assignedmedication becauseof side effects. Individ-
We did not
ing patients' diaries and lozenge count. We did not ual patients must decide whether the possible ben-
it difficult
check zinc or calcium blood levels, but it is difficult eficial effects of zinc on their cold symptoms out-
have
to predict whether these levels would have been weigh the possible adverse effects.
~ave several
meaningful, given tbat these elements have several Our data suggestthat zincgluconate in tile fQrm
other dietary sources. and dosage tested was helpful in reducing the du-
is
The fourth limitation of our study is that our our ration of common cold symptoms. Although we
results cannot be applied to immunocompromised
ompromised used a lower dose of zinc, our results were nearly
or pregnant patients, because neither group was
group was identical to those reported by Godfrey and col-
not provide
included in our study. Fifth, we did not provide leagues in their subset of 44 patients who were
:he repeated
information on the cumulative effect of the repeated randomly assigned to a treatment similar to ours
use of zinc or explore the possibility of development
levelopment after fewer than 24 hours of symptoms.In addition,
of resistance. We emphasize that we. used only used ~nly multi-institution studies that obtain virologic data
~. Habitual
short-term zinc therapy for common colds. Habitual on the infecting organisms are needed to confirm
or long-term ingestion of large dosesof zinc may be
ZInc be our findings.
hazardousby causingimbalancesin levels of copper
Is of copper
(39) and possibly other nutrients. We also avoided
Ilso avoided Acknowledgments: authorsthankBectonDiclcinson
The (Ruther-
which have
zinc dosages greater than 150 mgld, which have ford, New Jersey)for supplyingthe digilal thermometers, the
) S' Oui&Iey Corp, (Doylestown.Pennsylvania) supplyina ac-
for the
been associatedwith adverse effec,ts(40). Sixth, al-
). ixth, al- live andplacebo medication,
McNeil (Fort Washington, Pennsyt-
though our results indicated clinical improvement
nprovement vania) for supplyingacetaminophen, aassia Restaurant
and
on cold, we
when zinc was used to treat the common cold, we (aeveland,Ohio) for donatinga dinner for two for a raJJe to
do not know the actual mechanism by, which this
which this encourage patients to enroU in the study. The authors also thank
' ed ' th h Jobn C, Godfrey,PhD, and NIDC)'J, Godfrey,PhD, for their
occurred. Finally, if patients had complied with the
I WI t e help in designing studyand reviewing manUlCript,
this the Tom
protocol (one lozenge every 2 hours while awake),
~ile awake), Langfor medical editing,and CharleneMahovlicfor typingthe
they would have taken sevenor eight lozengeseach
zenges each manuscript.
day. Zinc lozengeswere actually taken about four to
bout ~our GI'fIIII
Support: the GeneralPediatrics
By Researd1Fundandthe
). ThIS may
eight times daily (median, five lozenges).This may Departments InfectiousDiseases GeneralPediatrics
of and of
~ number of
raise concernsabout compliance, but the number of the aeveland Clinic Foundation,
lozenges taken appears to have been effective. A
effective. A &qums for &prints: MichaelL Macknin,MD, Departmentof
recent review (41) and a MEDLINE search showed
arch showed Pediatricsand AdolescentMedicine,A 120,OevelaodOink
no evidencethat calcium lactate causesadverse ef-
adverse ef- Foundation,9500Euclid Avenue,aeveland,OH 44195.
IS July 1996 . A1INJi.J llllmlill Medidne . Volume 125 . Number2
of 87
87

8. Cunmi Author Addrusu: DR. Mosaad and Macknin, Ms. Med. 19. lft ET. Statistical Methods for SurviYiI 0... ~. 2d Iditian NIw York:
endorp, and Ms. Muon: The ~Iand Oinic Foundation, 9SOO. Wiley; 1992:77.
Euclid Avenue, Oeveland, OH 44195. 20. Gr8nt A. ~ controlled trials. 8r J Obslltl GynecGI. t--:397-400.
21. The st.andIrds of reporting trials group. A ptOpOMI fof structurtd reporting of
randomized controlled trills. lAMA. 1994;272:1926-3t.
22. SchuIIICF. C1IIIm8n I. ...,.. IU. AhIMn DG. Empiric8 evidtnct of biIs
dimensions~
of ~ 8OCiIIed wilt! ~ of tNIImInt
References ~ects in controlledtnals lAMA. 1995;273:408-12.
n. SmIItI
-. W.();er.~ midrnecIUIion:
I cri1icIImiIW
1. DInfIe JH, Gf, JonI8n W5 II. IInessin 1M Home:5tudv 0125.000 of clinicaltrills ~ 1950and 1991.JAMA..1993;269:2258-63.
1IIn4!s~ a Groupof CIMand Families.
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Univ; 1964 mother. 1988;32:60S-6.
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III - """..lat"", " ..n.. n«, ,.. - --- .. ~ . .~_.
linn< an IIViIl<lrU1
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" ,,-- -
.. ." _W"-' - -_. ~...u. , .L..L.-
"'- or~..~
...~. ~~ '~.'~.'V'-'J. n
concenllationsproducedby diflerenl formulations zincgIuconaIe
of IoangIs
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I
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-
modIer. 1984;25:20-4. pII!JIe5anea common COk/trNtment !@SUItS
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01 sAmpltx virus
- -..
..
Chemother. 1987;20:893-901.
... -
.- . .. '-".. . ... -- -
.. -- -- ...
u -..,
- ..
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88 IS July 1996 . Annals of Inlemal Medk:iM . Volume125 . Number 2