Benzodiazepines for alcohol withdrawal (Review) - machealth.ca

112 Pages·2010·1.32 MB·English

Benzodiazepines for alcohol withdrawal (Review)
Amato L, Minozzi S, Vecchi S, Davoli M
ThisisareprintofaCochranereview,preparedandmaintainedbyTheCochraneCollaborationandpublishedinTheCochraneLibrary
2010,Issue3
http://www.thecochranelibrary.com
Benzodiazepinesforalcoholwithdrawal(Review)
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Figure9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Figure10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Figure11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure12. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Figure13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Figure14. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Figure15. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
ADDITIONALSUMMARYOFFINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 28
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Benzodiazepinesforalcoholwithdrawal(Review) i
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Benzodiazepines for alcohol withdrawal
LauraAmato1,SilviaMinozzi1,SimonaVecchi1,MarinaDavoli1
1DepartmentofEpidemiology,ASLRM/E,Rome,Italy
Contact address: Laura Amato, Department of Epidemiology, ASL RM/E, Via di Santa Costanza, 53, Rome, 00198, Italy.
[email protected].
Editorialgroup:CochraneDrugsandAlcoholGroup.
Publicationstatusanddate:Newsearchforstudiesandcontentupdated(conclusionschanged),publishedinIssue3,2010.
Reviewcontentassessedasup-to-date: 18May2005.
Citation: AmatoL,MinozziS,VecchiS,DavoliM.Benzodiazepinesforalcoholwithdrawal.CochraneDatabaseofSystematicReviews
2010,Issue3.Art.No.:CD005063.DOI:10.1002/14651858.CD005063.pub3.
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Alcohol abuse and dependence represents a serious health problem worldwide with social, interpersonal and legal interpolations.
Benzodiazepineshavebeenwidelyusedforthetreatmentofalcoholwithdrawalsymptoms.Moreoveritisunknownwhetherdifferent
benzodiazepinesanddifferentregimensofadministrationmayhavethesamemerits.
Objectives
Toevaluatetheeffectivenessandsafetyofbenzodiazepinesinthetreatmentofalcoholwithdrawal.
Searchstrategy
CochraneDrugsandAlcoholGroup’RegisterofTrials(December2009),PubMed, EMBASE, CINAHL(January1966toDecember
2009),EconLIT(1969toDecember2009).Parallelsearchesonwebsitesofhealthtechnologyassessmentandrelatedagencies,and
theirdatabases.
Selectioncriteria
Randomizedcontrolledtrialsexaminingeffectiveness,safetyandrisk-benefitofbenzodiazepinesincomparisonwithplaceboorother
pharmacologicaltreatmentandbetweenthemselves.Allpatientswereincludedregardlessofage,gender,nationality,andoutpatientor
inpatienttherapy.
Datacollectionandanalysis
Twoauthorsindependentlyscreenedandextracteddatafromstudies.
Mainresults
Sixtyfourstudies,4309participants,mettheinclusioncriteria.
-Comparingbenzodiazepinesversusplacebo,benzodiazepinesperformedbetterforseizures,3studies,324participants,RR0.16(0.04
to0.69),nostatisticallysignificantdifferencefortheotheroutcomesconsidered.
-Comparingbenzodiazepinesversusotherdrugs,thereisatrendinfavourofbenzodiazepinesforseizureanddeliriumcontrol,severe
lifethreateningsideeffect,dropouts,dropoutsduetosideeffectsandpatient’sglobalassessmentscore. Atrendinfavourofcontrol
Benzodiazepinesforalcoholwithdrawal(Review) 1
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
groupwasobservedforCIWA-Arscoresat48hoursandattheendoftreatment.Theresultsreachstatisticalsignificanceonlyinone
study,with61participants,resultsonHamiltonanxietyratingscalefavourcontrolMD-1.60(-2.59to-0.61)
-Comparingdifferentbenzodiazepinesamongthemselves,resultsneverreachedstatisticalsignificancebutchlordiazepoxideperformed
better
-Comparingbenzodiazepineplusotherdrugversusotherdrug,resultsneverreachedstatisticalsignificance.
-Inthecomparisonoffixed-scheduleversussymptom-triggeredregimens,resultsfromasinglestudy,with159participants,favour
symptom-triggeredregimensMD-1.10[-3.27,1.07]forCIWA-Arscoresattheendoftreatment.Differencesinisolatedtrialsshould
beinterpretedverycautiously.
Authors’conclusions
Benzodiazepinesshowedaprotectivebenefitagainstalcoholwithdrawalsymptoms,inparticularseizures,whencomparedtoplacebo
andapotentiallyprotectivebenefitformanyoutcomeswhencomparedwithotherdrugs.Nevertheless,nodefiniteconclusionsabout
theeffectivenessandsafetyofbenzodiazepineswaspossible,becauseoftheheterogeneityofthetrialsbothininterventionsandthe
assessmentofoutcomes.
PLAIN LANGUAGE SUMMARY
Benzodiazepinesforalcoholwithdrawal
Benzodiazepines are more effective than placebo against alcohol withdrawal seizures while they have variable profile against other
commonlyusedtreatments
This Cochrane review summarizes evidence from sixty-four randomised controlled trials evaluating the effectiveness and safety of
benzodiazepinesinthetreatmentofalcoholwithdrawalsymptoms.Theavailabledatashowthatbenzodiazepinesareeffectiveagainst
alcoholwithdrawalseizureswhencomparedtoplaceboandapotentiallyprotectivebenefitformanyoutcomeswhencomparedwith
otherdrugs.Dataonsafetyoutcomesaresparseandfragmented.
Benzodiazepinesforalcoholwithdrawal(Review) 2
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
CoBe SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation]
pn
yrzo
ighdia
tz
©ep
2010ines BenzodiazepineversusPlaceboforalcoholwithdrawal
Tfo
hr
eCochraalcoholw PSInaettetitreinvnegtnso:triopno:pBuelanztioodni:azpeaptiiennetsvewrsituhsaPlclaocheoblowithdrawal
neith
Cd
ollaboration.rawal(Review Outcomes IAllsussutmraetidverisckomparativerisCkosr*re(s9p5o%ndCinI)grisk R(9e5la%tivCeI)effect N(sotuodfiePsa)rticipants Q(GuRaAlitDyEo)ftheevidence Comments
P)
u
b
lis Control Benzodiazepine versus
h
ed Placebo
b
y
Jo
h Alcohol withdrawal Studypopulation RR0.16 324 ⊕⊕⊕(cid:13)
n
W seizures (0.04to0.69) (3studies) moderate1
ile objective 80per1000 13per1000
y
& (3to55)
S
o
n
s
,L Mediumriskpopulation
td
.
69per1000 11per1000
(3to48)
Adverseevents Studypopulation RR3.28 71 ⊕⊕(cid:13)(cid:13)
(0.31to34.52) (2studies) low2,3
28per1000 92per1000
(9to967)
Mediumriskpopulation
46per1000 151per1000
(14to1000)
Dropouts Studypopulation RR0.68 312 ⊕⊕⊕(cid:13)
(0.38to1.24) (3studies) moderate1
3
CB
oe
pn
yrzo
ighdia
tz 162per1000 110per1000
©ep
2010ines (62to201)
Tfo
hera Mediumriskpopulation
Cochralcoholw 167per1000 114per1000
neith (63to207)
Cd
ora
llaboration.wal(Review *aCsTI:shuCemobneafdisdirseisnfkcoerinitnhthteeeravcsaosl;muRmpRae:rdisRorisinskkgrra(oetiu.ogp;.atnhdetmheedreialnatcivoenterfoflegctrooufpthreisikntaecrvroesnstiosntu(daineds)itsis9p5r%ovCidIe).dinfootnotes. Thecorresponding risk(andits95%confidence interval) isbasedonthe
P)
u
b
lis GRADEWorkingGroupgradesofevidence
h
ed Highquality:Furtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect.
b
y Moderatequality:Furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmaychangetheestimate.
Jo
h Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate.
n
W Verylowquality:Weareveryuncertainabouttheestimate.
ile
y
& 1Allocationconcealmentunclearfor2/3studies
So 2onlytwostudies,limitednumberofparticipants
n
s, 3Largeconfidenceinterval
L
td
.
4
BACKGROUND
Howtheinterventionmightwork
Benzodiazepineshavebeenshowntobeoneofthemosteffective
classofdrugsinthemanagementofalcoholwithdrawalsyndrome.
Descriptionofthecondition Therationaleoftheuseofbenzodiazepine istomodulateCNS
hyperactivity,interactingwithGABAreceptors,duetothealcohol
Alcohol abuse and dependence represents a most serious health
withdrawal.
problemworldwidewithmajorsocial,interpersonalandlegalin-
terpolations.Dependenceonalcoholisassociatedwithbothphys-
iological symptoms such as tolerance and withdrawal, and be-
haviouralsymptomssuchasimpairedcontroloverdrinking(Hasin
Whyitisimportanttodothisreview
1990). Alcohol withdrawal syndrome is a cluster of symptoms
thatoccursinalcohol-dependentpeopleaftercessationorreduc- Thepurposeofthissystematicreviewwastoexaminetheevidence
tioninalcoholusethathasbeenheavyorprolonged.Theclinical on the effectiveness and safety of benzodiazepines in the man-
presentationvariesfrommildtoseriousandtheonsetofsymp- agementof alcohol withdrawal. Resultsof aprevious version of
tomstypicallyoccursafewhoursafterthelastalcoholintake.The aCochrane Systematicreview (Ntais 2005)on benzodiazepines
mostcommonmanifestationsaretremor,restlessness,insomnia, efficacyandsafetyarenotconclusive.Newtrialshavebeenpub-
nightmares, paroxysmal sweats, tachycardia, fever,nausea, vom- lishedandthereviewneedsupdate.
iting,seizures,hallucinations(auditory,visual,tactile),increased Areaofuncertainty:noconclusiveevidenceofcomparativeeffec-
agitation, tremulousnessanddelirium.Thesesymptomsinvolve tivenessbetweenbenzodiazepineandothermedications.
a wide range of neurotransmitter circuits thatare implicated in Thisreviewhasaparalleloneonanticonvulsantsforalcoholwith-
alcohol tolerance and reflect a homeostatic readjustment of the drawal(Minozzi2010)andtogethertheyarepartofaseriesofre-
centralnervoussystem(DeWitte2003;Koob1997;Nutt1999; viewsandprotocolsontheefficacyofpharmacologicaltreatment
Slawecki1999).Long-termalcoholconsumptionaffectsbrainre- (AcamprosateGHB,nitrousoxide,magnesium)foralcoholwith-
ceptorsthatundergoadaptivechangesinanattempttomaintain drawal(Gillman2007;Leone2010;Fox2003;Tejani2010)
normalfunction.Someofthekeychangesinvolvereducedbrain
gamma-aminobutyric acid (GABA) levels and GABA- receptor
sensitivity (Dodd 2000; Gilman 1996; Kohl 1998; Petty 1993)
and activation of glutamate systems (Tsai 1995), which lead to
nervoussystemhyperactivityintheabsenceofalcohol.Thead- OBJECTIVES
vances in knowledge of neurobiology and neurochemistry have
promptedtheuseofdrugsinthetreatmentofalcoholdependence Theobjectivesofthissystematicrevieware:
andwithdrawalthatactthroughtheseGABApathways.
1. Toevaluatetheeffectivenessofbenzodiazepinesinthe
treatmentofalcoholwithdrawal.
Descriptionoftheintervention
2. Toevaluatethesafety(potentialarms)ofbenzodiazepines
Benzodiazepinesinparticularhavebeenwidelyusedforthetreat- inthetreatmentofthealcoholwithdrawalsymptoms(AWS).
mentofalcoholwithdrawalsymptoms.Ameta-analysisofstud-
ies concerning pharmacological therapies of alcohol withdrawal
(Mayo-Smith1997)hassuggestedthatbenzodiazepinesareeffec-
METHODS
tive in reducing withdrawal severity, incidence of delirium and
seizureswithagreatermarginofsafetyandlowerabusepotential
whencomparedtoothertherapies.
Amorerecentsystematicreview(Holbrook1999)ofrandomised
controlled trials (RCTs) comparing benzodiazepines to placebo Criteriaforconsideringstudiesforthisreview
or other therapy reached similar conclusions. However a large
amountofevidenceofbenzodiazepineusehasbeenpublisheddur-
ingthelastyearsanditisimportantthatanup-to-datesystematic
Typesofstudies
review is performed. Moreover not all patients may need phar-
macologicaltreatmentanditisunknownwhetherdifferentben- RandomizedControlledTrials(RCT)andControlledClinicalTri-
zodiazepinesanddifferentregimensofadministration(e.g.fixed als(CCT)evaluatingtheefficacy,safetyandoverallrisk-benefitof
versussymptom-triggeredschedule)mayhavethesamemerits. benzodiazepinesforthetreatmentofalcoholwithdrawal.
Benzodiazepinesforalcoholwithdrawal(Review) 5
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Typesofparticipants Secondaryoutcomes
Alcoholdependentpatientsdiagnosedinaccordancewithappro- 1. Additionalmedicationneeded
priate standardized criteria (e.g., criteria of Diagnostic and Sta- 2. Lengthofstayinintensivetherapy
tisticalManual ofMentalDisorders(DSM-IV-R)orICD)who 3. Mortality
experiencedalcoholwithdrawalsymptomsregardlessofthesever- 4. Qualityoflife
ityofthewithdrawalmanifestations. Allpatientswereincluded
regardlessofage,gender,nationality,andoutpatientorinpatient
therapy.Thehistoryofprevioustreatmentswasconsidered,butit Searchmethodsforidentificationofstudies
wasnotaneligibilitycriterion.
Electronicsearches
Typesofinterventions Relevanttrialswereobtainedfromthefollowingsources:
-Experimentalintervention 1. CochraneDrugsandAlcoholGroup’RegisterofTrials
• Benzodiazepinesaloneorincombinationwithotherdrugs (December2009)
2. PubMed(January1966-December2009)
-ControlIntervention 3. EMBASE(January1988-December2009)
• Placebo;Otherpharmacologicalinterventions 4. CINAHL(January1982-December2009)
5. EconLIT(1969toDecember2009)
-Typesofcomparisons Wecompileddetailedsearchstrategiesforeachdatabasesearched,
1. benzodiazepinesversusplacebo; fordetailseeAppendix1;Appendix2;Appendix3;Appendix4
2. benzodiazepinesversusotherdrug
3. differentbenzodiazepinesbetweenthemselves;
Searchingotherresources
4. benzodiazepinescombinedwithotherdrugversusother
Wealsosearched:
drug.
1. thereferencelistsofallrelevantpaperstoidentifyfurther
studies.
2. conferenceproceedingslikelytocontaintrialsrelevantto
Typesofoutcomemeasures
thereview.
We contacted investigators seeking information about unpub-
lishedorincompletetrials.Allsearchesincludednon-Englishlan-
Primaryoutcomes guage literatureandstudieswithEnglishabstracts wereassessed
Efficacyoutcomes forinclusion.Whenconsideredlikelytomeetinclusioncriteria,
1. Alcoholwithdrawalseizuresasnumberofsubjects studiesweretranslated.
experiencingseizures
2. Alcoholwithdrawaldeliriumasnumberofsubjects
experiencingdelirium Datacollectionandanalysis
3. Alcoholwithdrawalsymptomsasmeasuredbyprespecified
scales(astheCIWA-Arscore)
4. Globalimprovementofoverallalcoholwithdrawal Selectionofstudies
syndromeasmeasuredinpre-specifiedscales(asnumberof
Twoauthorsindependentlyscreenedthetitlesandabstractsofall
patientswithglobalimprovement,globaldoctorsassessmentof publications,obtainedthroughthesearchstrategy.Allpotentially
efficacy,Patientsassessmentofefficacy) eligiblestudieswereobtainedasfullarticlesandtwoauthorsinde-
5. Cravingasmeasuredbyprespecifiedscales pendentlyassessedtheseforinclusion.Indoubtfulorcontrover-
Safetyoutcomes sialcases,allidentifieddiscrepancieswerediscussedandreached
1. Adverseeventsasnumberofsubjectsexperiencingatleast
consensusonallitems.
oneadverseevent
2. Severe,life-threateningadverseeventsasmeasuredby
Dataextractionandmanagement
numberofsubjectsexperiencingsevere,lifethreateningadverse
events Twoauthorsindependentlyextracteddatafrompublishedsources,
Acceptabilityoutcomes where differences in data extracted occurred this was resolved
1. Dropout through discussion. Whererequiredadditional information was
2. Dropoutduetoadverseevents obtainedthroughcollaborationwiththeoriginalauthors.
Benzodiazepinesforalcoholwithdrawal(Review) 6
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Assessmentofriskofbiasinincludedstudies Assessmentofreportingbiases
The riskof bias assessment for RCTs and CCTs in thisreview Funnel plot(plotof theeffectestimate fromeachstudy against
wasperformedusingfouroutofthesixcriteriarecommendedby the sample size or effect standard error) was not used to assess
theCochraneHandbbok(Higgins2008).Therecommendedap- thepotentialfor biasrelatedtothesizeof thetrials, because all
proachforassessingriskofbiasinstudiesincludedinCochraneRe- the included studies had small sample size and not statistically
viewisatwo-parttool,addressingfourspecificdomains(namely significantresults.
sequence generation, allocation concealment, blinding, incom-
pleteoutcomedata).Thefirstpartofthetoolinvolvesdescribing Datasynthesis
what was reported to have happened in the study. The second
The outcomes from the individual trials have been combined
partofthetoolinvolvesassigningajudgementrelatingtotherisk
throughmeta-analysiswherepossible(comparabilityofinterven-
ofbiasforthatentry.Thisisachievedbyansweringapre-speci-
tionandoutcomesbetweentrials)usingafixedeffectmodelunless
fiedquestionabouttheadequacy ofthestudyinrelationtothe
therewassignificantheterogeneity,inwhichcasearandomeffect
entry,such thatajudgementof “Yes”indicates lowriskof bias,
modelhavebeenused.
“No”indicateshighriskofbias,and“Unclear”indicatesunclear
If all arms in a multi-arm trial are to be included in the meta-
orunknownriskofbias.Tomakethesejudgmentswewillusethe
analysis and one treatment arm is to be included in more than
criteriaindicatedbythehandbookadaptedto theaddictionfield.
oneofthetreatmentcomparisons,thenwedividedthenumberof
SeeAppendix5fordetails.
eventsandthenumberofparticipantsinthatarmbythenumber
Thedomainsofsequencegenerationand allocationconcealment
oftreatmentcomparisonsmade.Thismethodavoidthemultiple
(avoidance of selection bias) will be addressed in the tool by a
useofparticipantsinthepooledestimateoftreatmenteffectwhile
singleentryforeachstudy.
retaininginformationfromeacharmofthetrial.Itcompromise
Blindingofparticipants,personnelandoutcomeassessor(avoid-
theprecisionofthepooledestimateslightly.
anceofperformancebiasanddetectionbias)wasconsideredsep-
aratelyforobjectiveoutcomes(e.g.dropout,dropoutduetoad-
verseevents,seizures,delirium,adverseevents)andsubjectiveout- Sensitivityanalysis
comes(e.g.durationandseverityofsignsandsymptomsofwith- Toassesstheeffectofmethodological quality ontheresults,we
drawal,craving,psychiatricsymptoms;improvementsassessedby firstperformedagraphicalinspectionofanyeffectsortingthere-
doctorsandpatients). sultsontheforestplotsaccordingtoriskofbiasforsequencegen-
Incompleteoutcomedata(avoidanceofattritionbias)wasconsid- eration, allocation concealment, blinding (subjective outcomes)
eredforalloutcomesexceptforthedropoutfromthetreatment, ; if we found a difference in the results between studies at low,
whichisveryoftentheprimaryoutcomemeasureintrialsonad- unclear,highriskofbias,weperformedasensitivityanalysisex-
diction. cludingstudiesathighriskofbias.
Measuresoftreatmenteffect
RESULTS
DichotomousoutcomeswereanalysedcalculatingtheRelativerisk
(RR)foreachtrialwiththeuncertaintyineachresultbeingex-
pressedbytheirconfidenceintervals.Continuousoutcomeswere
Descriptionofstudies
analysedcalculatingtheMDortheSMDwith95%CI.Incaseof
missingstandarddeviationofthedifferencesfrombaselinetothe See:Characteristicsofincludedstudies;Characteristicsofexcluded
endoftreatment,thestandarddeviationwereimputedusingthe studies;Characteristicsofstudiesawaitingclassification.
standarddeviationofthemeanattheendoftreatmentforeach
group.
Resultsofthesearch
Weidentified695reportsfromallelectronicdatabasessearched
excludingduplicate,603wereexcludedonbasisoftitleandab-
Assessmentofheterogeneity
stract; 1articleisawaiting classification because wecannot find
Statistically significant heterogeneity among primary outcome thefulltext,91articleswereretrievedinfulltextformoredetailed
studieswillbeassessedwithChi-squared(Q)testandI-squared evaluation,27ofwhichwereexcluded,64satisfiedallthecrite-
(Higgins2008).AsignificantQ(P<.05)andI-squaredofatleast riatobeincludedinthereview.SeeFigure1toseeaflowchart
50%willbeconsideredasstatisticalheterogeneity showingidentificationofstudies.
Benzodiazepinesforalcoholwithdrawal(Review) 7
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Figure1. Flowchartofidentifiedstudies
Krupitsky2007;Lapierre1983;Lenzenhuber1999;Lepola
Includedstudies
1984;Longo2002;Lucht2003;Malcolm1989;Malcolm2002;
64 studies met the inclusion criteria, with a total of 4309 par- Malcolm2007;McGrath1975;Nava2007;Overall1973;
ticipants.Foradescriptionofthecharacteristicsoftheincluded Palestine1976;Pena-Ramos1977;Pena-Ramos1979;
studies,SeeCharacteristicsofincludedstudiesTable Radouco-Thomas1989;Runion1978;Sellers1977;Stuppaeck
Countryoforiginoftheincludedstudies 1992;Tubridy1988;Worner1994).
26studieswereconductedinEurope,32inNorthAmerica,3in 3. Differentbenzodiazepinesbetweenthemselves(No.=18
Asia,2inSouthAfricaand1inAustralia studies)(Adinoff1994;Anton1997;Brown1972; Day2004;
Numberofstudiespertypeofcomparison Jauhar2000;Kolin1981;Kumar2009;Martin1975;McLendon
1. Benzodiazepinesversusplacebo(No.=11studies)(Adinoff 1980;Mendels1985;Mielke1976;Miller1984;Mukherjee
1994;Burroughs1985a;Kaim1969;Kaim1972;Krupitsky 1983;O’Brien1983;Ritson1986;Saletu1983;Solomon1983;
2007;Martin1975;McLendon1980;Mielke1976;Naranjo Wilson1985)
1983;Sellers1977;Sellers1983) 4. Benzodiazepinesaloneversusbenzodiazepinescombined
2. Benzodiazepinesversusotherdrug(No.=42studies) withotherdrug(No.=3studies)(Dion1968;Sellers1977;
(Addolorato1999;Addolorato2006;Adinoff1994;Bailly1992; Spies1996)
Baumgartner1987;Baumgartner1991;Borg1986;Burroughs Foramoredetailedinformationaboutthecomparisonsconsidered
1985a;Burroughs1985b;Choi2005;Dion1968;Favre2005; inthestudies,seeAddictionalTable1;Table2;Table3;Table4;
Funderburk1978;Gillman2004;Gillmer1973;Golbert1967; Table5;Table6
Kaim1969;Kaim1972;Kalyoncu1996;Kramp1978;
Benzodiazepinesforalcoholwithdrawal(Review) 8
Copyright©2010TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.