Pain management for inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing

28 Pages·2012·0.36 MB·English

Pain management for inflammatory arthritis (rheumatoid
arthritis, psoriatic arthritis, ankylosing spondylitis and other
spondyloarthritis) and gastrointestinal or liver comorbidity
(Review)
Radner H, Ramiro S, Buchbinder R, Landewé RBM, van der Heijde D, Aletaha D
ThisisareprintofaCochranereview,preparedandmaintainedbyTheCochraneCollaborationandpublishedinTheCochraneLibrary
2012,Issue2
http://www.thecochranelibrary.com
Painmanagementforinflammatoryarthritis(rheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisandother
spondyloarthritis)andgastrointestinalorlivercomorbidity(Review)
Copyright©2012TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 26
Painmanagementforinflammatoryarthritis(rheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisandother i
spondyloarthritis)andgastrointestinalorlivercomorbidity(Review)
Copyright©2012TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Pain management for inflammatory arthritis (rheumatoid
arthritis, psoriatic arthritis, ankylosing spondylitis and other
spondyloarthritis) and gastrointestinal or liver comorbidity
HelgaRadner1,SofiaRamiro2,3,RachelleBuchbinder4,RobertBMLandewé3,5,DésiréevanderHeijde6,DanielAletaha1
1DivisionofRheumatology,DepartmentofInternalMedicine3,MedicalUniversityVienna,Vienna,Austria.2DepartmentofRheuma-
tology,HospitalGarciadeOrta,Almada,Portugal.3DepartmentofClinicalImmunology&Rheumatology,AcademicMedicalCen-
tre, Amsterdam, Netherlands. 4Monash Department of Clinical Epidemiology at Cabrini Hospital, Department of Epidemiology
and Preventive Medicine, School of PublicHealth and Preventive Medicine, Monash University, Malvern, Australia. 5Department
ofRheumatology,AtriumMedicalCentre,Heerlen,Netherlands.6DepartmentofRheumatology,LeidenUniversityMedicalCenter,
Leiden,Netherlands
Contactaddress:HelgaRadner,DivisionofRheumatology,DepartmentofInternalMedicine3,MedicalUniversityVienna,Waehringer
Guertel18-20,Vienna,1090,[email protected].
Editorialgroup:CochraneMusculoskeletalGroup.
Publicationstatusanddate:Edited(nochangetoconclusions),publishedinIssue2,2012.
Reviewcontentassessedasup-to-date: 15January2011.
Citation: RadnerH,RamiroS,BuchbinderR,LandewéRBM,vanderHeijdeD,AletahaD.Painmanagementforinflammatory
arthritis (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other spondyloarthritis) and gastrointestinal or liver
comorbidity.CochraneDatabaseofSystematicReviews2012,Issue1.Art.No.:CD008951.DOI:10.1002/14651858.CD008951.pub2.
Copyright©2012TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Evenwithoptimaldisease-modifyingtreatmentandgoodcontrolofdiseaseactivity,persistentpainduetostructuraldamageiscommon
inpeoplewithinflammatory arthritisandthereforeadditional treatmentforpainmightberequired.Becausecomorbidity ishighly
prevalentinpeoplewithinflammatoryarthritis,itisimportanttoconsidercomorbiditiessuchasgastrointestinalorliverdiseasesin
decidinguponoptimalpharmacologicpaintherapy.
Objectives
Toassesstheefficacyandsafetyofpharmacologicalpaintreatmentinpatientswithinflammatoryarthritiswhohavegastrointestinalor
livercomorbidities,orboth.
Searchmethods
WesearchedCochraneCENTRAL,MEDLINEandEMBASEforstudies,toJune2010.WealsosearchedtheAmericanCollegeof
Rheumatology(ACR)andtheEuropeanLeagueAgainstRheumatism(EULAR)conferenceabstracts(2007to2010)andperformed
ahandsearchofreferencelistsofarticles.
Selectioncriteria
Allrandomisedorquasi-randomisedcontrolledtrials(RCTsorCCTs)wereconsideredforinclusion,fortheassessmentofefficacy.For
safety,wealsoconsideredsinglearmtrials,controlledbefore-afterstudies,interruptedtimeseries,cohortandcase-controlstudies,and
caseseriesof10ormoreconsecutivecases.Paintherapycomprisedparacetamol,non-steroidalanti-inflammatorydrugs(NSAIDs),opi-
oids,opioid-likedrugs(tramadol)andneuromodulators(antidepressants,anticonvulsantsandmusclerelaxants).Thestudypopulation
Painmanagementforinflammatoryarthritis(rheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisandother 1
spondyloarthritis)andgastrointestinalorlivercomorbidity(Review)
Copyright©2012TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
comprisedadults(≥18years)withrheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisorotherspondyloarthritiswhohad
gastrointestinalorhepatic,orboth,comorbidconditions.Outcomesofinterestwerepain,adverseeffects,functionandqualityoflife.
Studiesthatincludedamixedpopulationofinflammatoryarthritisandotherconditionswereincludedonlyifresultsforinflammatory
arthritiswerereportedseparately.
Datacollectionandanalysis
Tworeviewauthorsindependentlyselectedtrialsforinclusion,assessedriskofbiasandextracteddata.
Mainresults
From2869identifiedarticlesonlyonesinglearmopentrialfulfilledourinclusioncriteria.Thistrialassessedthesafetyandefficacyof
naproxen(dosagenotspecified)in58patientswithactiverheumatoidarthritisandgastrointestinalcomorbiditiesforupto52weeks.
Thirteenparticipants(22%)remainedongoldtherapy,fourparticipants(10%)remainedonhydroxychloroquine,27(47%)remained
oncorticosteroids,12(21%)remainedonsalicylatesandallparticipantscontinuedonantacidsandablanddiet.Thepresenceoffaecal
occultbloodwasreportedin1/58participantstestedbetweenweeks1to26and2/32participantstestedbetweenweeks27to52.Over
thecourseofthestudy,sevenparticipants(12.1%)withdrewduetoadverseeventsbut,ofthese,onlytwoparticipantswithdrewdue
togastrointestinalsideeffects(abdominalpainn=1,nausean=1)andnoseriousadverseeventswerereported.Itwasnoteablethat
outof14studiesexcludedduetoinclusionofamixedpopulation(osteoarthritisorotherrheumaticconditions)oranintervention
thatwasalreadywithdrawn,fivetrialsreportedahigherriskofdevelopinggastrointestinaleventsinpatientswithpriorgastrointestinal
eventswhentreatedwithNSAIDs.
Authors’conclusions
On the basis of the current review, there is scant evidence to guide clinicians about how gastrointestinal or liver comorbidities
shouldinfluencethechoiceofpaintreatmentinpatientswithrheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisorother
spondyloarthritis.Baseduponadditionalstudiesthatincludedamixedpopulationofparticipantswitharangeofrheumaticconditions,
NSAIDsshouldbeusedcautiously inpatients withinflammatory arthritisandahistory ofgastrointestinaI comorbidity asthereis
consistentevidencethattheymaybeatincreasedrisk.
PLAIN LANGUAGE SUMMARY
Paininpatientswithinflammatoryarthritisandgastrointestinalorliverproblems
Thissummary ofaCochrane reviewpresentswhatweknowfromresearchabout theeffectofpainrelievingdrugsforpeoplewith
inflammatoryarthritisplusstomachorgutdisease,orliverdisease.
Thereviewshowsthefollowinginpeoplewithinflammatoryarthritisplusstomachorgutdisease,suchasherniaorstomachorintestinal
ulcersorpreviousbleedingfromthestomachorintestine,orpatientswithliverdiseasessuchashepatitisorfattyliver:
-Weareuncertainifnaproxen(Aleve®,Naprosyn®)producedmoresideeffectsinpeoplewithinflammatoryarthiritisplusstomach
orintestinedisease,comparedwithpeoplewithinflammatoryarthritiswithoutstomachorintestinedisease,becauseonlyasinglestudy
givinglowqualityevidencewasavailable.
-Nostudieswerefoundthatlookedatpainrelief.
-Nostudieswerefoundthatlookedatotherpain-relievingdrugs.
-Nostudieswerefoundinpeoplewithconditionsotherthanrheumatoidarthritis.
-Nostudieswerefoundinpeoplewithinflammatoryarthritisplusliverdisease.
Wedonothavepreciseinformationaboutsideeffectsandcomplications,particularlyforrarebutserioussideeffects.Possiblesideeffects
associatedwithhighdoseparacetamolincludeliverproblems.AspirinandNSAIDsmaycausestomach,kidneyorheartproblems.
Whatisinflammatoryarthritisandwhatispainmanagement
Inflammatory arthritisisagroupof diseasesthatincludesrheumatoidarthritis,ankylosing spondylitis, psoriaticarthritisandother
typesofspondyloarthritis.Whenyouhaveinflammatoryarthritisyourimmunesystem,whichnormallyfightsinfection,attacksyour
joints.Thismakesyourjointsswollen,stiffandpainful.Inrheumatoidarthritis,thesmalljointsofyourhandsandfeetareusually
Painmanagementforinflammatoryarthritis(rheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisandother 2
spondyloarthritis)andgastrointestinalorlivercomorbidity(Review)
Copyright©2012TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
affectedfirst.Incontrast,inankylosingspondylitisthejointsofthespinearethemostaffected.Thereisnocureforinflammatory
arthritisatpresent,sothetreatmentsaimtorelievepainandstiffnessandimproveyourabilitytomove.
Paracetamol,oracetaminophen,isusedtorelievepainbutdoesnotaffectswelling;non-steroidalanti-inflammatorydrugs(NSAIDs)
suchasibuprofen,diclofenac,naproxenandCOX-2s(forexamplecelecoxib)areusedtodecreasepainandswelling.Opioids,suchas
codeine-containingTylenol®,hydromorphone(Dilaudid®),oxycodone(Percocet®,Percodan®),morphineandtheopioid-likedrug
tramadolarepowerfulpain-relievingsubstances.Otherdrugshavesomepain-relievingpropertiesandcanthereforebeusedtocontrol
pain. This isthecase of theso-calledneuromodulators, such asantidepressants (for examplefluoxetine, paroxetine, amitriptyline),
anticonvulsants(forexamplegabapentine,pregabaline)ormusclerelaxants(forexamplediazepam).
BACKGROUND
observationalregistryofIAindicatesthatabouttwothirdsofpa-
tientsstartingbiologictherapyforRAorAShavecomorbidities
Descriptionofthecondition atbaselineandapproximatelyonethirdself-reportthepresenceof
gastrointestinaldisease(Briggs2009;Oldroyd2009).Therefore,
Chronic inflammatory arthritis (IA) of various types are com-
the consideration of comorbidities and the risk associated with
mon, affecting about 3% of the population (Bergmann 2006).
themisimportantwhenprescribingmedicationstoalleviatepain
ThespectrumofIAincludesdiseasessuchasrheumatoidarthri-
forpatientswithIA.
tis(RA),psoriaticarthritis(PsA),ankylosingspondylitis(AS)and
otherformsofspondyloarthritis(SpA).TypicallyIAischaracter-
izedbyaprogressivecourseofsynovialinflammation leadingto
joint destruction (Drossaers-Bakker 1999), which can be effec-
tivelytreatedbydiseasemodifyingantirheumaticdrugs.However, Howtheinterventionmightwork
despitesignificantprogressinthedevelopmentofnewtherapeu-
Twocommoncomorbidities toconsiderincludegastrointestinal
tics,includingthebiologics,painthatiseitherrelatedorunrelated
andhepaticdisease.Manydrugshaveanoralrouteofapplication
todiseaseactivitypersistsinmanypatientscausingsubstantialim-
andgastrointestinaladverseeventsarecommoncausesforstopping
pairmentofphysicalfunctionandqualityoflife(Bergmann2006;
thesemedications (Boswell2010;Ng2010).Inaddition, many
Minnrock2003).
drugsaremetabolisedbytheliver,whichmightthereforeincrease
theriskofadverseevents,especiallyinpatientswithknownliver
disease.
Descriptionoftheintervention
Althoughsuppressinginflammationistheprimarytargetfortreat-
mentofIA,maintaining functional integrityisitsultimategoal
(Smolen2010).Treatingpainisthusacrucialsteptoachievethis
Whyitisimportanttodothisreview
goalanddrugsthatmaybeusedforthispurposeincludeparaceta-
mol, non-steroidal anti-inflammatory drugs (NSAIDs), opioids In patients with IA, regardless of disease activity, pain manage-
and opioid-like drugs (such as tramadol) and neuromodulators ment is a central issue. It is identified by patients to be among
(includingantidepressants,anticonvulsantsandmusclerelaxants). theirhighestpriorities(daSilva2001;Heiberg2002).Thisreview
Someofthesetherapies,suchastheNSAIDs,havebeenastan- isoneoftworeviewsthataimtosummarisetheexistingdataon
dard treatment in IA as they can improve symptoms, although theefficacyandsafetyofpharmacologicalpaintreatmentinpa-
theyhavelimitedimpactondiseaseprogression(Emery2006). tientswithIAwhoalsohavecomorbidities.Thisreviewfocuseson
Whiletheregularuse ofthesemedicationsinotherwisehealthy thecoexistenceofgastrointestinalorhepaticcomorbiditywhilea
individualsisnotwithoutrisk,thepotentialfortoxicityislikelyto secondreviewfocusesoncardiovascularandrenalcomorbidities
beincreasedinpatientswithpre-existingcomorbidities.Patients inpatientswithrheumatoidarthritis(Marks2010).Theissueof
withIAareatanincreasedriskofdevelopingextensivecomorbid painmanagementinIApatientswithgastricorlivercomorbidities
conditions (Gabriel 1999; Michaud 2007) not only due to the hasnotyetbeenaddressedinasystematicreview,hencereviewing
longcourseoftheinflammatorydiseaseprocessbutalsobecause existingevidenceshouldprovideimportantinformationforclin-
ofadvancedageovertime.Forexample,datafromanAustralian iciansaswellaspatients.
Painmanagementforinflammatoryarthritis(rheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisandother 3
spondyloarthritis)andgastrointestinalorlivercomorbidity(Review)
Copyright©2012TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
OBJECTIVES • Safety:numberofwithdrawalsduetoadverseevents.
To assess the efficacy and safety of pharmacologic pain therapy
in patients with IA (RA, PsA, AS, SpA)who have concomitant
Minoroutcomes
gastrointestinalorhepaticdisease,orboth.
Thefollowingoutcomeswerealsoincluded.
• Safety:
◦ worseningofcomorbidcondition(forinstance
METHODS
recurrenceofulcerbleeding,worseningofendoscopygradeof
ulcers,increaseinserumtransaminases);
◦ anyadverseevents;
Criteriaforconsideringstudiesforthisreview
◦ withdrawalsduetoinadequateanalgesia.
• Pain:
◦ participant-reportedpainreliefof30%orgreater;
Typesofstudies ◦ participant-reportedglobalimpressionofclinical
Allpublishedrandomisedcontrolledtrials(RCTs) orcontrolled change(PGIC)’much’or’verymuch’improved;
clinicaltrialswithpseudo-randomisedmethodsofallocatingtreat- ◦ proportionofpatientsachievingapainscorebelow
ment(CCTs)wereconsideredforinclusion,forassessmentofef- 30/100mmonavisualanaloguescale;and
ficacy. ◦ meanpainscoreonavisualanaloguescaleor
Toassesssafety,wealsoconsideredcontrolledbefore-afterstud- numericalratingscale.
ies(CBA),interruptedtimeseries(ITS),singlearmtrials,cohort • Function:forRA,forexample,asmeasuredbytheHealth
studies,case-controlstudiesandcaseseries.Thecaseserieshadto AssessmentQuestionnaire(HAQ)ormodifiedHAQ(Fries
haveatleast10casesfollowedconsecutivelytobeincluded. 1980;Pincus1983),orforASbytheBathAnkylosing
Onlystudiesthatwerepublishedasfullarticlesorwereavailable SpondylitisFunctionalIndex(BASFI)(Calin1994);
asafulltrialreportwereincluded.Therewerenolanguagerestric- • Qualityoflife:asmeasuredbyeithergenericinstruments,
tions. suchastheShort-Form-36(SF-36)(Ware1992),ordisease-
specifictoolssuchastheRheumatoidArthritisQualityofLife
instrument(RAQoL)(Doward2003)andAnkylosing
Typesofparticipants
SpondylitisQualityofLifeInstrument(ASQoL)(Jong1997).
Weselectedstudiesincludingadultsofatleast18yearsofagewith
Thepainoutcomeswerechosenbaseduponthosecurrentlyrec-
aclinicaldiagnosisofeitherRA,AS,PsAorSpA,andareported
concomitantgastrointestinalorhepaticcomorbidcondition.For ommendedbytheCochranePain,PalliativeandSupportiveCare
controlledstudiesweincludedstudiesthatincludedparticipants ReviewGroupeditorsandothersforsystematicreviewsonchronic
withandwithoutgastrointestinalorhepaticcomorbidities.Studies pain (Moore 2010). However, the primary efficacy endpoint of
participant-reportedpainreliefof50%orgreaterwaschosento
thatincludedamixedpopulationofIAandotherconditionswere
beconsistentwiththerecommendationsoftheCochraneMuscu-
includedonlyiftheresultsforIAwerereportedseparately.
loskeletalGroupforchoiceofsummaryoffindingsoutcomesto
presentforreviewsinRA.
Typesofinterventions Theoutcomeswereevaluatedforthefollowingendpointsifavail-
Interventions that were included were paracetamol (ac- ableintheincludedstudies:(a)short-term(1to6weeks),(b)in-
etaminophen),NSAIDs,opioidsoropioid-likedrugs(tramadol) termediate-term(>6to12weeks),and(c)long-term(>12weeks)
andneuromodulators,includingantidepressants,anticonvulsants follow-up. These intervals were chosen based upon the recom-
andmusclerelaxants.Thesedrugswereconsideredirrespectiveof mendationsofMooreetal(Moore2010).
route,dosage,frequencyordurationoftreatment.Drugsthathad Theshortandlong-termoutcomesfortheproportionreporting
beenwithdrawnfromthemarketplacewereexcluded. painreliefof50%orgreater,withdrawalsduetoadverseeffects,
adverse events, and worsening of the comorbid condition were
chosenaprioritobepresentedinthesummaryoffindingstable.
Typesofoutcomemeasures
Searchmethodsforidentificationofstudies
Majoroutcomes
• Efficacy:participant-reportedpainreliefof50%orgreater,
reportedonvisualanaloguescales,numericalratingscale,verbal
Electronicsearches
ratingscales.
Painmanagementforinflammatoryarthritis(rheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisandother 4
spondyloarthritis)andgastrointestinalorlivercomorbidity(Review)
Copyright©2012TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Thefollowingelectronicdatabaseswereusedtoidentifyrelevant ForstudiespublishedinlanguagesotherthanEnglish,German,
studies:theCochraneCentralRegisterofControlledTrials(CEN- Portuguese,French,SpanishorDutch,thehelpofanativespeaker
TRAL)(TheCochraneLibrary2010,Issue6);MEDLINE(from ortranslatorwithcontentandmethodologicalexpertisewasob-
1950);andEMBASE(from1980),withoutlanguagerestrictions. tained,asnecessary.
Theliteraturesearchwaslastupdatedon18June,2010.
Specific MeSH headings and additional keywords were used to
Assessmentofriskofbiasinincludedstudies
identifyallrelevantstudies.Thecompletesearchstrategiesforthe
databasesearchesareprovidedintheAppendices(MEDLINEand The potential for bias in included RCTs and CCTs was to be
CENTRALsearchstrategy:Appendix1,EMBASEsearchstrategy: assessed independently by two review authors (HR, SR) using
Appendix2). methodsrecommendedbyTheCochraneCollaboration(Higgins
2011b).Thefollowingitemsweretobeassessed:
• randomsequencegeneration;
Searchingotherresources • allocationconcealment;
To ensure that all potential studies were identified we also per- • blindingofparticipants,careproviderandoutcomeassessor
formed a search in the Cochrane Database of Systematic Re- foreachoutcomemeasure(seeTypesofoutcomemeasures);
views (CDSR) and the Database of Abstracts of Reviews of Ef- • incompleteoutcomedata;
fects(DARE).Wemanuallysearchedthebibliographiesofallin- • selectivereporting;and
cludedpapersforinformationonanyotherrelevantstudies.We • otherpotentialsourcesofbias.
also handsearchedthe conference proceedings for the American
To determine the risk of bias of a study, for each criterion the
CollegeofRheumatology(ACR)andtheEuropeanLeagueagainst
presenceofsufficientinformationandthelikelihoodofpotential
Rheumatism(EULAR)(2007 to2010) toidentify unpublished
biasweretobeevaluated.Eachcriterionwastoberatedaslowrisk
studies.
ofbias,highriskofbiasorasunclear(eitherlackofinformationor
uncertaintyoverthepotentialforbias).Disagreementsamongthe
reviewauthorsweretobediscussedandresolvedinaconsensus
Datacollectionandanalysis
meeting.Ifconsensuscouldnotbereached,athirdreviewauthor
(RB)wastomakethefinaldecision.
ForCBAsandITS,weplannedtousethecriteriadescribedbythe
Selectionofstudies Cochrane Effective Practice and Organisation of Care (EPOC)
Tworeviewauthors(HR,SR)independentlyscreenedeachtitle Group,whichdescribessevenstandardcriteriaforeachofthese
and abstract for suitability of the study for inclusion in the re- studytypes,scoredasdone,notdoneornotclear(EPOC2008).
view.Theydecided,independentofeachother,theeligibilityof Forcohortandcase-controlstudies,weplannedtousetheNew-
thearticleaccording tothepredeterminedselectioncriteria(see castle-OttawaScale(NOS)(Wells2008),whichassessesbiasac-
Criteriaforconsideringstudiesforthisreview).Ifmoreinforma- cordingtoselection,comparabilityandoutcome.
tionwasneededtodecideupontheeligibilityofthestudies,the Forcaseseries,theguidancerecommendedbytheCentreforRe-
fulltextofthepaperwasobtained.Reasonsforexcludingstudies views andDissemination (CRD 2001) was tobe used.Thisas-
weredocumentedanddisagreementbetweenthereviewauthors sessesthefollowingcriteria.
wasresolvedbyconsensus,oraftertheinputofthethirdauthor • Isthestudybasedonarepresentativesampleselectedfrom
(DA)whohadthefinaldecision. arelevantpopulation?
• Arethecriteriaforinclusionexplicit?
• Didallindividualsenterthesurveyatasimilarpointin
Dataextractionandmanagement theirdiseaseprogression?
Twoindependentreviewauthors(HRandSR)extracteddatafrom • Wasfollow-uplongenoughforimportanteventstooccur?
the included studies onto a standardised form. Information ex- • Wereoutcomesassessedusingobjectivecriteriaorwas
tractedincludedstudydesign,characteristicsofstudypopulation, blindingused?
characteristicsofcomorbidcondition,treatmentregimenanddu- • Ifcomparisonsofsubseriesarebeingmade,wasthere
ration,outcomesincludingadverseeventsandtimingofoutcome sufficientdescriptionoftheseriesandthedistributionof
assessment.Therawdata(meansandstandarddeviationsforcon- prognosticfactors?
tinuous outcomes and number of events or participants for di-
chotomousoutcomes)wereextractedfortheoutcomesofinterest.
Measuresoftreatmenteffect
Differencesindataextractionwereresolvedbyreferringbacktothe
originalarticlesandestablishingconsensus.Athirdreviewauthor Rawdataforoutcomesofinterest(meansandstandarddeviations
(DA)wasconsultedtohelpresolvediscrepancies,asneeded. forcontinuousoutcomesandnumberofeventsfordichotomous
Painmanagementforinflammatoryarthritis(rheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisandother 5
spondyloarthritis)andgastrointestinalorlivercomorbidity(Review)
Copyright©2012TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
outcomes)aswellasnumberofparticipantsweretobeextractedif HandbookforSystematicReviewsofInterventions(Higgins2011a).
availablefromthepublishedreports.Theresultsofthestudieswere If standard deviations could not be calculated, they were to be
tobeanalysedandcollatedusingReviewManager5.Summarising imputed (for example from other studies) in the meta-analysis
the data in a meta-analysis was planned only if the data from (Higgins2011c).
the different studies were sufficiently clinically and statistically
homogeneous.
For continuous data, results were planned to be analysed as Assessmentofheterogeneity
meandifferencesbetweentheinterventionandcomparatorgroups As we included non-randomised studies in this review to assess
(MD),withcorresponding95%confidenceintervals.Themean safety,we considered thatheterogeneity was likelyto be greater
differencebetweenthetreatedgroupandcontrolgroupisweighted thanifRCTsalonewereincluded,andwewouldbelesslikelyto
bytheinverseof thevariance inthepooledtreatmentestimate. be abletopool our findings quantitatively. We plannedtoonly
However,ifdifferentscaleswereusedtomeasurethesameconcep- poolstudieswiththesamedesign.
tualoutcome(forexamplefunctionalstatusorpain),weplanned Prior to meta-analysis, we planned to assess studies for clinical
to calculate standardised mean differences (SMD) with corre- homogeneitywithrespecttotypeoftherapy,controlgroupand
sponding95%confidenceintervals.SMDsweretobecalculated theoutcomes.Foranystudiesjudgedasclinicallyhomogeneous,
bydividingtheMDbythestandarddeviation,resultinginaunit- statistical heterogeneitywas planned to be assessed using theI2
lessmeasureoftreatmenteffect.A95%CIwouldbecomputedfor statistic (Deeks 2011) using the following as a rough guide for
theSMDand,uponcompletionoftheanalysis,theSMDwould interpretation:0%to40%mightnotbeimportant,30%to60%
betranslatedbackintoameandifference.Fordichotomousdata, mayrepresentmoderateheterogeneity,50%to90%mayrepresent
arelativerisk(RR),oddsratios(OR)orhazardratio(HR)with substantialheterogeneity,and75%to100%considerablehetero-
corresponding95%confidenceintervalwasplannedtobecalcu- geneity. In cases of considerable heterogeneity (defined as I2 ≥
lated,asappropriate. 75%),weplannedtoexplorethedatafurther,includingsubgroup
analyses,inanattempttoexplaintheheterogeneity.
Unitofanalysisissues
Unitofanalysisproblemswerenotexpectedinthisreview.Inthe Assessmentofreportingbiases
eventthatcross-overtrialswereidentifiedinwhichthereporting In order to determine whether reporting bias was present, we
ofcontinuousoutcomedataprecludedpairedanalysis,thesedata plannedto identify if the protocolsof any includedRCTs were
werenottobeincludedinameta-analysisinordertoavoidunit- publishedbeforerecruitmentofpatientsintothestudywasstarted.
of-analysiserror.Wherecarry-overeffectswerethoughttoexist, Forstudiespublishedafter1July2005,weplannedtoscreenthe
andwheresufficientdataexisted,onlydatafromthefirstperiod ClinicalTrialsRegisterattheInternationalClinicalTrialsRegistry
wereplannedtobeincludedintheanalysis(Higgins2011c). PlatformoftheWorldHealthOrganization(http://apps.who.int/
trialssearch)(DeAngelis2004).Weplannedtoevaluatewhether
selectivereporting of outcomes was present (outcome reporting
Dealingwithmissingdata bias).
If any important data were missing, we planned to contact the We planned to compare the fixed-effect model estimate against
studyauthors. therandom-effectsmodeltoassessthepossiblepresenceofsmall
Fordichotomousoutcomesthatmeasuredadverseevents(forex- samplebiasinthepublishedliterature(thatiswheretheinterven-
amplenumberofwithdrawalsduetoadverseevents),thenumber tioneffectismorebeneficialinsmallerstudies).Inthepresence
ofpatientsthatreceivedtreatmentwastobeusedforthedenomi- ofsmallsamplebias,therandom-effectsmodelestimateofthein-
nator(worstcaseanalysis).Fordichotomousoutcomesthatmea- terventionismorebeneficialthanthefixed-effectmodelestimate
suredbenefits(forexampleproportionofparticipantsachieving (Sterne2011).
30%ormorereductioninpain),theworstcaseanalysiswastobe Thepotentialforreportingbiaswasplannedtobefurtherexplored
calculatedusingthenumberofparticipantsasthedenominator. byfunnelplotsif≥10studieswereavailable.
Forcontinuousoutcomes(forexamplepain),weplannedtocal- We did not identify sufficient trials to assess reporting bias as
culatetheMDorSMDbasedonthenumberofpatientsanalysed planned.
atthetimepoint.Ifthenumberofpatientsanalysedwasnotpre-
sentedforeachtimepoint,thenumberofrandomisedpatientsin
Datasynthesis
eachgroupatbaselinewasplannedtobeused.
Wherepossible,missingstandarddeviationsweretobecomputed Wherestudiesweresufficientlyhomogeneousthatitwasclinically
fromotherstatisticssuchasstandarderrors,confidenceintervalsor meaningfulforthemtobepooled,meta-analysiswasplannedus-
Pvalues,accordingtothemethodsrecommendedintheCochrane ingarandom-effectsmodel,regardlessoftheI2 statistic results.
Painmanagementforinflammatoryarthritis(rheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisandother 6
spondyloarthritis)andgastrointestinalorlivercomorbidity(Review)
Copyright©2012TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
However,wedidnotidentifysufficientstudiestoperformmeta- outcomes(numberofwithdrawalsduetoadverseevents,shortand
analysis. long-termoutcomesforpain,functionandworseningofcomorbid
conditions), asrecommendedbyTheCochraneCollaboration(
Schünemann2011a).Itwouldincludeanoverallgradingofthe
Subgroupanalysisandinvestigationofheterogeneity
evidencerelatedtoeachofthemainoutcomes,usingtheGRADE
Sufficientdatawerenotavailabletoundertakeplannedsubgroup approach(Schünemann20011b).
analyses:
• differencesbetweendifferentcomorbidconditionsand
theirseverity(e.g.ulcerbleedingversusdyspepsia);
• differencesbetweentypeofIA(RAversusAS,PsA,SpA); RESULTS
• Patients’ages(<65yearsversus≥65years).
Descriptionofstudies
Sensitivityanalysis See:Characteristicsofincludedstudies;Characteristicsofexcluded
Sufficient studies were not identified to performplanned sensi- studies.
tivityanalyses:toassesstheimpactofanybiasattributabletoin- See:Characteristicsofincludedstudies,Characteristicsofexcluded
adequateoruncleartreatmentallocation(includingstudieswith studies
pseudo-randomiseddesigns).
Resultsofthesearch
Summaryoffindingstable A total of 2869 articles were identified by the search strategy
The plannedsummary of findings table couldnot be produced (Figure1).Afteratitleandabstractscreen,2795articleswereex-
duetoalackofstudies.Thetablewouldprovidekeyinformation cluded.Of73articlesretrievedfordetailedreview,onlyonestudy
concerning the quality of evidence, the magnitude of effect of fulfilledtheinclusioncriteria(Roth1975)(seeCharacteristicsof
theinterventionsexamined,andthesumofavailabledataonthe includedstudies).
Painmanagementforinflammatoryarthritis(rheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisandother 7
spondyloarthritis)andgastrointestinalorlivercomorbidity(Review)
Copyright©2012TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Figure1. Flowchartoftheresultsofthesearchstrategy,outliningthemainreasonsforstudyexclusion.
wasalsoreported.Therewasnoindicationofwhoperformedthe
Includedstudies
outcomeassessmentandtheexacttimingofoutcomeassessment
Roth1975included58patientswithactiveRAandconcomitant wasnotspecifiedbutitwasreportedasoccurringatbaselineand
uppergastrointestinaIcomorbiditiesinanopensinglearmtrial. inweeks1to26andweeks27to52.
ThegastrointestinaIcomorbiditiesweredefinedas’gastrointesti- The mean ages of females and males were reported to be 50.8
naldysfunctionofvaryingdegreesofseverity’.Inaddition,thepa- and 52.0 yearsrespectively,meandisease duration was reported
tientswerereportedtohaveanintolerancetoanti-inflammatory tobe170monthsormore,and62.1%ofthestudypopulation
medication.Toassessthesafetyofnaproxeninthiscohortofpa- werefemale.Thirteenparticipants(22%)remainedongoldther-
tients,participantsinthetrialreceivednaproxen(dosagenotspec- apy,fourparticipants(10%)remainedonhydroxychloroquine,27
ified)forupto52weeks.Participantswereallowedtocontinue (47%) remained on corticosteroids and 12 (21%) remained on
onstablemaintenancedosesofcorticosteroids,goldorantimalar- salicylates.ThetypesofgastrointestinaIdysfunctioninthecohort
ials. All other NSAIDs were discontinued but salicylates, while includedhiatushernia(asdeterminedbyuppergastrointestinalx-
discouraged,werepermittedprovidedtheirusewasreported.In rayexaminationatbaseline)(n=40),gastriculcer(n=12),duo-
addition,patientscontinuedonantacidsandablanddiet. denalulcer(n=23),gastrichypersecretion(n=25),pylorospasm
Themainoutcomesofthestudy,asidentifiedintheresults,were (n=12),gastritis(n=8)andgastricresection(n=6).Twenty-six
gastrointestinalsideeffectsassessedbyfaecaloccultbloodtesting, participantshadbothahiatusherniaandeitheragastricorduode-
sideeffectsandsideeffectsleadingtodiscontinuationoftreatment. nalulcerwhile10participantshadallthree.Anumberofpartic-
Responsetotreatmentwasalsoevaluatedaccordingtothenumber ipants’werereportedtohavehaduppergastrointestinaIbleeding
ofpainfulortenderjoints,numberofswollenjoints,numberof problemspriortoenteringthestudy.
hot or redjoints, number of clinically active joints; therapeutic
response to naproxen on a scale of poor, fair, good or excellent
Painmanagementforinflammatoryarthritis(rheumatoidarthritis,psoriaticarthritis,ankylosingspondylitisandother 8
spondyloarthritis)andgastrointestinalorlivercomorbidity(Review)
Copyright©2012TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.