Reprinted from ANNALS OF INTERNAL MEDICINE Vol.125;No.2, 15 July 1996                                                  Pri...
thesestudiesshowedthat zinc had a beneficialef::-these studies showed that zinc had a beneficial ef::-      the studyas sp...
in the zinc group correctly determine that they were    _b. 1.     DemographicCharacteristics 99 Volunteers               ...
signrnent (P > 0.2). Even when the 17 nonadherent                                                        . patients were e...
cipients (16%) and 12 zinc recipients (25%) re-                                                                       -   ...
.--          iI.      .>U" ""...~           n...pun...   UJ ~   YUIUn_n          ~"IiI                 preVIous           ...
ability of zinc to help relievesymptoms the com- - fects in the dosesused in our study.Thus, we do                        ...
Cunmi Author Addrusu: DR. Mosaad and Macknin, Ms. Med.                                      19. lft ET. Statistical Method...
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Zinc Gluconate Lozenges for Treating the Common Cold: a Randomized, Double-Blind, Placebo-Controlled Study


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“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.

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Zinc Gluconate Lozenges for Treating the Common Cold: a Randomized, Double-Blind, Placebo-Controlled Study

  1. 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 InternalMedicineZinc Gluconate Lozengesfor Treating the Common ColdA Randomized,Double-Blind, Placebo-ControlledStudySherif B. Mossad,MD; Michael L. Macknin, MD; Sharon V. Medendorp, MPH;and PamelaMason, BSN, MBABackground: The common cold is one of the most fre- P < 0.001),nausea(20% compared with 4%; P "" 0.02), andquent 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 thebut evidence suggeststhat several possible mechanisms common cold. The mechanism of action of this substancemay make zinc an effective treatment. in treating the common cold remains unknown. IndividualObjectl".: 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 themon cold. possibleadverseeffects.Design: Randomized, double-blind, placebo-controlled AM Inlml M«l. 1996; From the OevelandOinic Foundation,aeveland, Ohio. ForSetting: Outpatientdepartmentof a largetertiary care current author addresses, see end of The common cold is one of the most frequentlyPatients: 100 employeesof the Cleveland Clinic who de- .1. occurring human illnesses in the world. Moreveloped 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 Statestaining 13.3mg of zinc from zinc gluconate as long asthey each year, adults develop an averageof two to fourhad cold symptoms. Patients in the placebo group (n - SO) colds and children develop an average of six toreceived similarly administered lozenges that contained eight colds (1, 2). The morbidity resulting from this5% calcium lactate penta hydrate instead of zinc glu- diseaseand the subsequentfinancial loss in terms ofconate. working hours are substantial (3). Many Outcome MHsures: Subjective daily symptom described treatments have not provided consistentscores cough, headache,hoarseness, for muscleache,nasal or well-documented relief of symptoms. Even adrainage, nasal congestion, scratchy throat. sore throat, treatment that is only partially effective in relievingsneezing,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 possibleplacebo group (median, 4.4 days compared with 7.6 days; mechanismsby which zinc may treat the commonP < 0.001). The zinc group had significantly fewer days cold, and seven controlled trials have studied thewith 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 oftion (4.0 daysand 6.0 days;P = 0.002), nasal drainage (4.0daysand 7.0 days;P < 0.001),and sore throat (1.0 day and3.0 days;P < 0.001).The groups did not differ significantlyin the resolution of fever, muscleache, scratchythroat, orsneezing. More patients in the zinc group than In theplacebo group had side effects (90% compared with 62%;
  2. 2. thesestudiesshowedthat zinc had a beneficialef::-these studies showed that zinc had a beneficial ef::- the studyas specified the protocolwere enrolled byfeet (4-6) and four did not (7-10). In the studiesfect (4-6) and four did not (7-10). In the studies in a ramefor one of two prizes:dinner for two orthat examinedthat examinedvirus shedding 7), zinc treatment virus shedding (5, 7), zinc treatment (5, a trip for two to the Bahamas. The Institutionalhad 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 gaveinformedand colleagues and used the symptomscoreand colleagues (6) and used the symptom score (6) consent the time of enrollment.Participants at weredevelopedby these researchers.developed by these researchers. We emphasized We emphasized informed of the placebo-controlled, double-blindstartingtreatmentstarting 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- forthat early treatmentwas most elective. We usedthat early treatment was most elective. We used rolled only if they had had cold symptoms 24 forzinc gluconatezinc gluconate lozenges, lozenges,which appeared be well which appeared to be well to hoursor less.Patients musthavehad at leasttwo oftoleratedand had the best bioavailabilitytolerated 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- orability, lozenges our studycontained13.3mg ofability, lozengesin our study contained 13.3 mg of in perature greater than 37.7°c. Patientswere ex-zinc. This provided a local concentrationof zinczinc. This provided a local concentration of zinc cludedif theywere pregnant, had a knownimmuneions of about4.4 mmo1/L, amountgreaterthanions of about 4.4 mmoVL, an amount greater than an deficiency, had had symptoms the common or ofthat necessary suppressthat 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 lozengeslactateso that it had a medicinaltaste similar tolactate so that it had a medicinal taste similar to were supplied by the Quigley Corporation ofthat 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 preparedwithmine 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- acold (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 andanismof any zinc elect. Althoughvirus culturesoranism of any zinc elect. Although virus cultures or lime flavoring oils. The mixture was formed intoserologictests might have been desirable,we de-serologic tests might have been desirable, we de- lozenges weighed4.4 g and contained13.3mg thatcidednot to do thesetestsbecausecided not to do these tests becausethey are almost they are almost of zinc. Placebo lozenges, weighing4.4 g, were alsoneverdonein 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 ofration of symptoms(in days) would representa medication. The packages were identicalin appear-significantclinical elect. A previousstudy of zinc ance exceptfor the randomizationnumbers.Thegluconate given during the first day of cold symp- studymedication distnDuted the studynurse, was bytomssuggested the duration of illnesswas re- that who wasmasked treatmentassignments. to Patientsducedfrom approximately days to 4 daysafter 8 weregiven 120lozenges were askedto dissolve andtreatmentbegan(6). Our previousresearch pa- on 1 lozenge their mouthsevery2 hourswhile awake intients with colds who were seen at the Oeveland for as long as they had cold symptoms. The studyClinic suggested the mean ~uration(:tSD) of that nurseadministered first lozenge assess the to initialcold symptoms was approximately :t 6 days (15, 7 tolerability.Participantswereasked takeno other to16).We chosea sample sizeof 100patientsso that cold preparationsduring the study period. Acet-we coulddetecta dilerence in the meannumberof aminophen samplesand oral digital thermometersdaysof symptoms from 8 daysin the placebo group weregivento the patientsat the time of 4 daysin the zinc group with a standarddevia- All patientswere calledon the second of med- daytion 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 toland ainic staftthroughannouncements internal in questionnaire. assessing adequacy the pla- By the ofOinic publications by word of mouth.One hun- and cebo on the secondday of treatmentrather thandred volunteers were enrolled between3 October only at the end of treatment, hopedto decrease weand 4 November 1994.All patientswho completed the likelihoodthat a rapid curewould help patients82 . 15July 1996 An1Ul1s InlenuUMediciM of . Volume 125 . Number2
  3. 3. in the zinc group correctly determine that they were _b. 1. DemographicCharacteristics 99 Volunteers of ReceivingZinc or PlaceboLozenges forreceiving the active medication. This questionnaire Treatmentof the CommonColdwas also administered at the end of treatment withthe addition of questions about the occurrence ofspecific, previously described side elects of zinctherapy. 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- Menenges so that adherence to the protocol could be women RIce. ~ nchecked through lozenge counts, and the study Whitenurse 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 ttWtions taken throughout the duration of their coldfor as long as 18 days. Every day, patients gradedeach symptom as 0 for none, 1 for mild, 2 formoderate, or 3 for severe. Total symptom scores )tom four or more lozengesper day for the first 4 daysofwere 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 resolution of all symptoms (a total symptom iiiscore of 0) or resolution of all but one mild symp-tom (a total symptom score of 1). ResultsStatistical 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 SOwerenumber of days from study entry. Resolution rates Ilution assigned to the placebo group. All patients werewere estimated using the Kaplan-Meier method, ier Oeveland Clinic employees older than 18 years ofand resolution profiles were compared between ~d age. One patient in the zinc group withdrew fromgroups using the log-rank test (17, 18). We esti- :). the study on the first day because she could notmated median resolution times using the method tolerate the lozenges; she did not complete thesuggestedby 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 hadthe number of days with each symptom using the n good tolerance of the first lozenge. DemographicWilcoxon 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 scoresatscratchythroat into a category called "throat symp- hroat baseline (the first measurement)were 8.6 ~ 3.3 andtoms" and nasal drainage and congestion into a tion 8 for the entire sample, 9.3:t 3.6 and 8 for thecategory called "nasal symptoms." Plots i of individ- placebo group, and 7.9 ~ 2.8 and 8 for the zincual patient symptoms give the percentage of the tage group. In practice, an increase in score from 8 to 9baselinetotal severity score (sum of symptom scores ptom entails scoring one symptom one grade higher orfor all patients) by assignmentgroup and study day. :I developing another mild symptom. Six hours afterWhen appropriate, we used the Fisher exact test r the study began, the mean symptom scores for theand the chi-square test to analyze associationsbe- ciations placebo group (9.3 ~ 4.2; median, 9) and the zinctween 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 baselinelozenge 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) andtreat 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 twoillnessother than the common cold were considered in the zinc group) had colds that did not resolvenonadherent. Patients who wrote their diaries from liaries while they remained in the study. Two of thesememory were also considerednonadherent. Patients :nt. patients (both were placebo recipients) completedwereconsidered 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. 4. signrnent (P > 0.2). Even when the 17 nonadherent . patients were excluded, symptoms in the zinc groupl 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 andi 3.9 days, respectively, for complete resolution andt 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, scratchyents) dropped out after 7 to 16 days. In addition, throat, sneezing, fever (Table 2). orone patient recorded his symptoms for 18 days but We calculated the total number of lozengesfromindicated 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 actualthe percentage of patients whose colds completely lozengecounts. During the entire study, the placeborf"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 ofrt: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 2group 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 placeboindicate that symptoms resolved significantly faster group used significantly more lozengesthan the zincin 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 placebowhether 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 othergroup 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 ofwhom also took antibiotic agents, and 4 placeborecipients) 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 nottolerate the taste of the medicine, and 2 placeborecipients) 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 notstated. When data were analyzed after these 17nonadherentpatients 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. 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 .55,715 zinc (6%) recipients reported a severe aftertaste. Two patients (1 in the placebo group and 1 in theFigure J. Percent8ge origin_I thlOllt symptoms,:- :::. d8y of - 88dI ~ zinc group) did not answer the trutment group. Throat symptomswere hoalSeness. 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 assignmentwere asked after the first day of Seventeen of 49 zinc recipients reported that notreatment and at the end of the study. Patientswere atients side effects developed with their medication beforeasked 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 untilbly placebo, do not know, certainly active, probably ve, only one mild symptom remained was the same asactive, or possibly active. By assigning all guesses aU the Dumber in the 32 patients with identified sidethat 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 daysing results were obtained. On the initial question- al and 5.5 days, respectively) and median (4.5 daysandnaire, 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 effects53.1 of the zinc recipients (20 of 49) correctly % 9) of zinc and asking patients at the end of the studyguessed their treatment assignment.Sixty-five of the y-five whether these or other side effects developed while99 patients (65.7%) maintained their original guess iginal they were taking the study medication (Table 3). Asat the end of the study. Becauseno clear pattern of Ir expected, patients described more side effects inmovement of guesses was seen between the groups,masking appears to have been maintained during inedthe study. T8bIe2. Duration individual of Symptoms the of After the first day of treatment, 46% of the pla- , of the pla- Common Coldcebo 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 Groupsymptoms(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- dtcipients said that the study medication had helped had helpedimprove 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 0.004zinc and placebo groups were subdivided IOto t e e into the Cough 4.5(1.10) 2.0(1.~ 0.04seven 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.G2patients were about their group assignmenton the Rent on e NISII congtStion 6.0(3.12) 4.0(2,6) 0.002first 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.OCI1tions of symptoms in the zinc group were a ays were always Muscleache 2.0 (1, 5) 1.0(0. 3) 0.11shorter 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.15t28 of 49 zinc recipients (57%) describedthe taste ofthe 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. 8IIdincluding 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. 6. .-- iI. .>U" ""...~ n...pun... UJ ~ YUIUn_n ~"IiI preVIous studJes that showed a beneficial effect ofT8bI. 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 ofVariable PIIcebo Group ZIncGroup onset of symptoms.Of the four studies that did notVariable 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 threeVomIting=:PIin I 12, ~g:0) 0 ~(&.1) studies that did show a beneficial effect, one (4)AbdomNI PIinDiaIThN . 1 (2.0) 2(4.0) 3 (&.1) 2(4.1) reported a strong treatment effect (P < 0.001)at 7DiIntI8I 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% ofMouthirritationBad.tIste 0.001>* (P 0.0011* < 10(20.0) 15 (30.0) 1212..5) 39(79.6) placebo recipients had symptomsat 7 days) but alsoe.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 0Dlymou1h 6(12.0) 6(12.2) This finding caused some investigators to questionDrymouIt1Other > 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"POI8d 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 lozengeresponse to this question than in response to theopen-ended question alone. Patients in the zinc was not distinguished from the zinc lozengeby tasteopen-ended question alone. Patients in the zincgroup reported more side effects per person (25 or reported more side effects per person (25zinc recipients and 5 placebo recipients had two or Godfrey and colleagues (6) compared a nonche-zinc recipients and 5 placebo recipients had two ormore side effects; P < 0.001), significantly moremore side effects; P < 0.001), significantly more lating formulation, zinc gluconate-glycine, which re-nausea (10 patients compared with 2 patients; 2nausea (10 patients compared with (39patients; leases93% of contained zinc in saliva, with a pia-P = 0.02), and more bad-taste reactions (39 patientsP = 0.02), and more bad-taste reactions patients cebo containing highly astringent tannic acid andcompared with 15 patients; P < 0.001). The other with 15 patients; P < 0.001), The other saccharin. They reported a 26% reduction in thecomparedsymptomsdescribed(vomiting, abdominal pain, diar-symptomsdescribed(vomiting, abdominal pain, diar- duration of colds when treatment was begun duringrhea, constipation, mouth irritation, and dry mouth) the second day of symptoms and a 42% reductionrhea, 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 theshowed that the time to resolution of all symptoms common cold remain to be determined, but severalwas significantly shorter in the zinc group. The zinc possibilities have been described. Zinc prevents thegroup had significantly fewer days with coughing, formation of viral capsid proteins, thereby inhibitingheadache,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 theeffects. The fact that zinc recipients and placebo carboxyl termini (negatively charged canyons) ofrecipients 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-surfaceproteincation 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 reproductionpatients 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 membraneson objective knowledge of the duration; this created by uncertain means (30, 33-36). In vitro studiesmuch variation in subjective estimates of whether have suggestedthat zinc may induce production ofthe 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 the86 . 15July 1996 Annals of InlmuJl MediciM . Volume 125 . Number2
  7. 7. ability of zinc to help relievesymptoms the com- - fects in the dosesused in our study.Thus, we do ofmon 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 havewhether 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 withingroups. 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 noting patients diaries and lozenge count. We did not ual patients must decide whether the possible ben- it difficultcheck zinc or calcium blood levels, but it is difficult eficial effects of zinc on their cold symptoms out- haveto predict whether these levels would have been weigh the possible adverse effects. ~ave severalmeaningful, given tbat these elements have several Our data suggestthat zincgluconate in tile fQrmother 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 weresults cannot be applied to immunocompromised ompromised used a lower dose of zinc, our results were nearlyor pregnant patients, because neither group was group was identical to those reported by Godfrey and col- not provideincluded in our study. Fifth, we did not provide leagues in their subset of 44 patients who were :he repeatedinformation on the cumulative effect of the repeated randomly assigned to a treatment similar to oursuse 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 ~. Habitualshort-term zinc therapy for common colds. Habitual on the infecting organisms are needed to confirmor 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 havezinc dosages greater than 150 mgld, which have ford, New Jersey)for supplyingthe digilal thermometers, the ) S Oui&Iey Corp, (Doylestown.Pennsylvania) supplyina ac- for thebeen 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, wewhen zinc was used to treat the common cold, we (aeveland,Ohio) for donatinga dinner for two for a raJJe todo 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 theiroccurred. Finally, if patients had complied with the I WI t e help in designing studyand reviewing manUlCript, this the Tomprotocol (one lozenge every 2 hours while awake), ~ile awake), Langfor medical editing,and CharleneMahovlicfor typingthethey would have taken sevenor eight lozengeseach zenges each Zinc lozengeswere actually taken about four to bout ~our GIfIIII Support: the GeneralPediatrics By Researd1Fundandthe ). ThIS mayeight times daily (median, five lozenges).This may Departments InfectiousDiseases GeneralPediatrics of and of ~ number ofraise 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, Departmentofrecent review (41) and a MEDLINE search showed arch showed Pediatricsand AdolescentMedicine,A 120,OevelaodOinkno 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. 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. in C~nd: Press Western~ of :M. GodfIwr JC. Zinc fof tht common cold (~~ AntimIcrobAgentseM- Univ; 1964 mother. 1988;32:60S-6. 2. Gw8l1ner JM Jr, Hendley 10, Simon G. .IonI8n WS Jr. Rhinovltu$ inlte- 25. u., GA. StabiIiIy conslantS of zonecornpiIIIrs .thct common mid tlWtmlnl III - """"", " ..n.. n«, ,.. - --- .. ~ . .~_. linn< an IIViIl<lrU1 1966;275":,261.., I ..- ", -.. III I UM results[Lener].AntimicrobAgentsehemolher. 1988;32:606-7. X. Z8Nmbo JE. Godhy JC. CicIdfNr IIU. Tone in NhI: deeInnination (I) of " ,,-- - .. ." _W"- - -_. ~...u. , .L..L.- "- or~..~ ...~. ~~ ~.~.V-J. n concenllationsproducedby diflerenl formulations zincgIuconaIe of IoangIs 4. Ibr CiA. D8WiI DII. H8IaIInb WW. Reduction in durMion of common cold cont.1ri1gcommonexcipients. PNrm SO.1992;81:128-30. I by zinc glucanate lozenges in a doubIHIind study. Antimicrob Agents CIw- 27. ,., ... fG. Gw8Itn8rJM Jr. StabIIty consunts zinccom- of - modIer. 1984;25:20-4. pII!JIe5anea common COk/trNtment !@SUItS I~~J. Anllmlcrob Agents CI1e- - - on. - 5. AI.fWdb W. IG,--- .. G,1yrNIDA.IropI¥IIIIs mocher. 1918;32:607. and trN1ment of rhinovirus colds wi1h zinc gIuconate lozenges. J Antimiaob - CionIDn /IIIfIrf6 IIedC8r ~ YJ. Y, Y. Inhibition herpes 01 sAmpltx virus - -.. .. Chemother. 1987;20:893-901. ... - .- . .. -".. . ... -- - .. -- -- ... u -.., - .. MI. Zinc gkjcOlllte IIId the common cold: I controlled diNC11study. J Int Med repIOtion in 8S(-1 eels by zinc ions Antimiaob AgentsChemoIher.19~; 8:377.80. 21. firpo EJ. EL Inhibition01foot and moudI ell.- virusand proaIp5Id Res. 1992;20:234-46. synthesis Zincions. ~ by r@pOrt. Arch ViroI. 1979;61:175-81. 7. - -, c- EM,I8tts Itf, 0I8Ib J, Mlnnefcw Gw8ltn8y Jr. A. .. .. Its*- II. L8dI8MwIII. ~ C. IC8rInIU. K8dI GoIOIicMM- TwornbniDd controIedtrills of ZincgIuconMrIozengt thlflpy of e.per- imentJllymduc8drllincMruscolds.AntimicrobAgentsChernother.1987;31: assoa.tedproItin kinase: desUbiliulion of the virus capsid and sIimWtion 1183-7. of the ~ INCtion by Zn2. J Viral 1989;63:~. I. DougI8II1M, HI. Mo«e IW. lIyan . IInnodI Q. Flilure of 31. Motf8t As. Going back to the fulln wi1h SINII ~ compounds tftervesant Zinc ICNte Iozengts 10 III« the courseof uppet"respAIiOry (Newsl Scienc».1993;26Ct91 0-2. trlet infectionin Austrabn ldults. AntimicrobAgentsChemoth8r.1987;31: 32. NovIdc SG.GodfNr J(. GodfNr NJ, ... How doesme: mocify the 1263.5. commoncold?CIinicJI observations implications and regilding mechanism of t. SmIth DS, Hellner Ic, Nuttlln a Jr, Collins M. RofwwIIA. GInIb8rg 1CtJon. ~ Med 1996;46:29S-302. U. membr- protectionby Cal . CA. A novetform of host defence: D. .. ... Flilurt of ZincgIuconMr in trNtment of ICUII!uppet"repiriIIOrf Irlet infections.AntimicrobAgentsChemother.1989;33:646-8. and W. Iiosd Rep. 1987;7:81-91.10.WeIInIaM JIIIoIII8II *b Ie. ". JE. "- UM..., SM. M. I8Ihfard a. AId8r GM. M8ne1rfn8G. MIcId8M MurphyJJ,,.. IU, H- I, .. 81. Zinc gluconate lozenges for common cokl. A cfou~-blind -- CA.~ dimagtby~ viruses, (Qj,IpIe...e<1t, tains. clirWo1Ilrio1Inan Uod III. 1--.17.77<l-1li1 - -- - -- ----.-------- and oth« cytoloxic 91"15. A common m«hmsm bIocUcI by dMIInt Qt.n. lCorent 10. ~ IE. InNbition by zinc of rhincMrusprOIIIn dNv- ions J BioI Chem. 1986;261:9300-8. .: interaction zincwith apsid polypeptides. VWoI. of I 1976;18:298-306. 35. H8riIdI Ii. 1CretIch- M. ~ aspectS of a non--- elect 01 zinc ions12.G8Ist --- Fe. JA.H8yIIen N. In vitro IC1MIyof zinc SIlls IgIinst on the histamine ~ from ral peritonNl mast ails. ~ (ommun (hem -- rlln7<inMS. Antimlcrob AgentsChemott1er. 1987;31:62H. Pathol and Phannacol. 1987;55:39-46.13. ~~ D, ~!-~~ .,.j pr~ attitudes lheripeUtlc In JI. --- Ii. fInII8y sa. LIch8IIIin LM. ModuIMions 01 basophil histamine,... s;;.;G..w;;E:~~M. Cost-eflectivenm compIri5ons using r.- byzinc (Abstta<tL J AIIttgy Clin 1mmunoI. 1979;65:171 37. 58181 M. IOrdIIw H. Induction 0I1n~1jiIMIa in human leutcocy18 "n!a wOOd"randomized triaI5:the caseof new antidepressant drugs.J CUn cu/1ures slimu1a1edby W. (Iin 1mmunoI1mmunopIIhoI. 1987;45:139-42. EpidemioIl996;48:363.7)15. ML. M8thew S. ..a.anclorp $V. Efleetof inhaledhNted vapor .. Ie" 1M. Abel MH. C~ and Zinc inhibit the metabolism of pro51agIan- on symptoms the commoncold. JAMA. 1990;264:~. 01 din by the human uterus. BioI RIprod. 1983;28:183-9". Font8II GJ, M8ckn1nML. Y8II-lIeb8nn8n .. MIl"" SV. Elled of ft. ~ cc. "".lInnou .. IoIII8r A. EtItct at cMInic zinc intaIIicJIion inhaled~aled vapor on Symptoms the commoncold. JAMA. i994;2": of on COpper IewIs.bloodfomIItion IIId poIytmines. ~ 0rttI0m0I 11W-!I I. 1980;9:79-89,17. IC8pIIn El. P. NonparIIMIric I5IiIMIion fftIm incDmpIeee ~ .. ~ lilt. bcesM inUh of Zinc impIirs inIIIIuM mpoIIws, lAMA, lions. ~ of the AmeriQn StItisIbI AssodItion. 1937;32:675-701. 1984;252: 144306-1L .. J. AsympIoIiaIIydiciInt ra ~ leStprocedures.Jour- .,. Optimal t*ium intake, NIH COIISIfISUS Confertnce, lAMA, 1994;272: nal of I~ Ro¥,1 Swlistiul Society Series A. 1972; 135: 185-98. 1942-888 IS July 1996 . Annals of Inlemal Medk:iM . Volume125 . Number 2