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Neurogastroenterology & Motility. 2019;31(Suppl. 2):e13605. | 1 of 29https://doi.org/10.1111/nmo.13605
Management of cyclic vomiting syndrome in adults: Evidence review
Ravi N. Sharaf1* | Thangam Venkatesan2* | Raj Shah3 | David J. Levinthal4 | Sally E. Tarbell5 | Safwan S. Jaradeh6 | William L. Hasler7 | Robert M. Issenman8 | Kathleen A. Adams9 | Irene Sarosiek10 | Christopher D. Stave11 | B U. K. Li12 | Shahnaz Sultan13
AbstractBackground: Thisevidencereviewwasconductedtoinformtheaccompanyingclini‐cal practice guideline on the management of cyclic vomiting syndrome (CVS) inadults.Methods: WefollowedtheGradingofRecommendationsAssessment,Development,andEvaluation(GRADE)frameworkandfocusedoninterventionsaimedatprophylac‐ticmanagementandabortivetreatmentofadultswithCVS.Specifically,thisevidencereviewaddressesthefollowingclinicalquestions:(a)Shouldthefollowingpharmaco‐logicagentsbeusedforprophylaxisofCVS:amitriptyline,topiramate,aprepitant,zon‐isamide/levetiracetam, or mitochondrial supplements? (b) Should the followingpharmacologicagentsbeusedforabortivetreatment:triptansoraprepitant?Results: We found very low‐quality evidence to support the use of the followingagents for prophylactic and abortive treatment of CVS: amitriptyline, topiramate,aprepitant, zonisamide/levetiracetam, and mitochondrial supplements. We havemoderatecertaintyofevidencefortheuseoftriptansasabortivetherapy.Wefoundlimitedevidencetosupporttheuseofondansetronandthetreatmentofco‐morbidconditions and complementary therapies.Conclusions: ThisevidencereviewhelpsinformtheaccompanyingguidelineforthemanagementofadultswithCVSwhich isaimedathelpingclinicians,patients,andpolicymakers,andshouldimprovepatientoutcomes.
Cyclic vomiting syndrome (CVS) is a chronic, debilitating illnessthatischaracterizedbyrecurrentepisodesofintensenauseaandvomiting. Although the true prevalence of CVS in adults in thegeneralpopulation remainsuncertain, it isnota raredisorder.Arecentpopulation‐basedstudynotedthattheUSprevalencewas2% among adults, mirroring prevalence estimates in children.1 Anotherestimatedthat~10%ofoutpatientspresentingtoater‐tiary gastroenterology clinicmet theRome III criteria for the ill‐ness;2however,even in thisclinicalsetting,CVSwasconsideredasapotentialdiagnosisinonlyasmallminorityofthesepatients.This finding highlights the poor recognition of CVS in adults byclinicians, with many patients continuing to suffer for severalyears before receiving a diagnosis ofCVS.Concertedmessagingand increasedawarenesscampaignsshouldminimize thisclinicalrecognitiongap.RecognizingCVSinadultsiscritical,asthereareseveralfairlyeffectiveprophylacticandabortivetherapiestotreatthe disorder.
This evidence review represents a foundational effort by theAmericanNeurogastroenterology andMotility Society (ANMS) andtheCyclicVomitingSyndromeAssociation(CVSA)todeveloprecom‐mendationsbasedontheGradingofRecommendationsAssessment,Development, andEvaluation (GRADE) framework toprovidea ro‐bust guideline for best practices in the management of CVS. Thisreviewaddressesfocusedclinicalquestionsontheuseofpharmaco‐logicagentsforprophylacticandabortivetherapiesforthemanage‐mentofpatientswithCVSandwasusedtoinformthedevelopmentoftheaccompanyingclinicalpracticeguidelines.Panelmemberswereselected by theCVS guideline committee task chair (T.V.), co‐chair(B.L.),andformerANMScouncilmember(B.M.)andtheCVSAbasedon their clinical andmethodological expertise.All members of thepanel underwent a thoroughvetting process for potential conflictsofinterest.
2 | METHODS
2.1 | Overview
This evidence reviewwas developed using the GRADE frameworkto develop clinically focused questions, and identify, synthesize,and evaluate the quality of the supporting evidence to inform arecommendation.3
2.2 | Formulation of clinical questions
Through an iterative process, the panel developed focused clinicalquestionsontheroleofspecifictherapeutics inthemanagementofCVS.ThePICOformatwasusedwhichframesaclinicalquestionbydefiningaspecificpopulation(P),intervention(I),comparator(C),andoutcomes (O) (Table 1). The populationwasadultpatientswithCVS.The interventionwasoneofnumeroustherapiesusedinCVS.Thepre‐ferred comparator was placebo. Relevant patient‐centered outcomes wereconsideredandratedintermsofimportance.AllPICOquestionsformedthebasisforaliteraturesearchwhichisdetailedbelow.
2.3 | Outcomes
Outcomesweregroupedintotwobroadcategoriesforprophylacticandabortivetherapies.Wearrivedataconsensusastowhatmeas‐urementswouldbeacceptable foreachoutcome.Outcomeswereratedbythegrouponascaleof1(notimportant)to9(criticallyim‐portant)formedicaldecisionmaking.Itwasunderstoodthatdataonall outcomes would not be available in the published literature.
2.4 | Systematic review process
2.4.1 | Search strategy
The literaturesearchwasperformed initially inJune2016andup‐dated in February 2018,with the aid of a research librarian (C.S.).
DetailsofthesearchstrategyarereportedintheOnlineSupplement.Individualstudieswereidentifiedviasearchesofthreebibliographicdatabases: PubMed (includesMEDLINE),SCOPUS (a large,multidis‐ciplinary database), andCINAHL(the Cumulative Index to Nursingand Allied Health Literature). Given the acknowledged possibilityofdiagnosticmisclassification, individualsearchstrategies includedthefollowingterms:cyclic vomiting; cyclical vomiting; cannabinoid hy‐peremesis; functional vomiting; abdominal migraine; and periodic syn‐drome.Thesearchesexcludedanimal‐onlystudiesandnon–Englishlanguage studies. The search strategy was iteratively developed throughrefinementwithauthorinputtomaximizesensitivity.Given
ForallPICOs, theapriori intentwas to relyuponhigh‐qualitysystematic reviews for evidence synthesis, particularly those thatsynthesizeddatafromrandomizedcontroltrials(RCTs).IfsystematicreviewsofRCTswerenotavailable,wewouldthenlooktoindividualRCTstogeneratesummaryestimatesifpossible.IntheabsenceofsystematicreviewsofRCTsorindividualRCTs,systematicreviewsofobservational studies and observational studies were then consid‐eredtoinformtheevidence.Caseseriesoffewerthan10individualswereexcluded,aswerenarrativereviews.
ThereviewersutilizedthePreferredReportingItemsforSystematicReviews and Meta‐analyses (PRISMA) guidelines to develop thereview.APRISMAflowdiagramis included inFigure1.Thetitles/abstractsfromthedatabasesearcheswereuploadedtoCovidence(http://covidence.org), a Web‐based application that facilitatesscreening and reviewing studies for systematic reviews. All titlesand abstracts were screened by two researchers (R.S. and S.S.) with disagreementsregardinginclusionandexclusionresolvedbydiscus‐sion. Inclusion criteria included any articles that might be relevant tothe includedPICOquestions.Exclusioncriteriawereprincipallyaroundstudydesignasmentionedabove.Atotalof1469non‐du‐plicatearticleswerefound,and572full‐textarticleswerethenre‐viewed.Oneauthor(R.S.)extracteddatafromfull‐textarticlesintoastandardizeddatacollectionformwithaccuracyofdataextractionconfirmedbyseveralmembersofthesystematicreviewcommittee.StudycharacteristicsanddataextractionarereportedinTable2a,b.
2.5 | Statistical analysis
Given the size andheterogeneityof included studies, themajorityofresults were suitable to narrative summary. Quantitative outcomes were calculated using Open Meta (http://www.cebm.brown.edu/openmeta/).
2.6 | Quality or certainty of evidence
TheGRADEapproachwasusedtoratethecertaintyintheevidence.Inthisapproach,directevidencefromRCTsstartsathighqualityandcanberateddownto levelsofmoderate, low,andvery lowquality,basedonriskofbiasinthebodyofevidence(orstudyquality), indi‐rectness (addressingadifferentbutrelatedpopulation, intervention,oroutcome, from theoneof interest), imprecision (of the summaryestimateandboundariesof95%CI),inconsistency(orheterogeneityintheresultsoftheincludedstudies),and/orpublicationbias.Duetoin‐herentlimitationsinobservationalstudies(selectionbias,unmeasuredconfounding,etc.),evidencederivedfromobservationalstudiesstartsatlowqualityandthenispotentiallydowngradedbasedontheafore‐mentionedfactorsorupgradedincaseofdose‐responserelationshipandlargemagnitudeofeffect.High‐qualityevidencesuggeststhatweareconfidentofthequalityoftheevidenceand/orthedirectionandmagnitudeof the effect estimate, and anynewdata are unlikely toalterthis.Moderatecertaintysuggeststhatwearemoderatelyconfi‐dentintheeffectestimate:Thetrueeffectislikelytobeclosetotheestimateoftheeffect,butthereisapossibilitythatitissubstantiallydifferent.Lowcertaintysuggeststhatourconfidenceintheeffectesti‐mateislimited:Thetrueeffectmaybesubstantiallydifferentfromtheestimateoftheeffect.Finally,verylowcertainty:Wehaveverylittleconfidenceintheeffectestimate:Thetrueeffectislikelytobesub‐stantiallydifferentfromtheestimateofeffect.Judgmentsaboutthecertaintyintheevidenceweremadeviadiscussionamongthepanel,and any disagreements were resolved by group consensus.
StudydetailsarepresentedinTable2a,bandsummarizedforeachPICOquestionintheaccompanyingevidenceprofiles.TheteamacknowledgesthelimitedevidenceforCVSwithfewrandomizedcontroltrialsorhigh‐quality observational studies leaving us with low‐ or very low‐quality cer‐taintyintheevidenceacrossoutcomes.Giventhepaucityofliteratureonthetopic,studiesofallpopulations (adultandpediatric)were includedwith the assumption that the pathophysiology of CVSwas similar inadultsandadolescents,andthattheeffectsofthevariousinterventionsmaybegeneralizableacross somepopulations.Finally, therewasvari‐abilityincriteriausedtodiagnoseCVS,medicationexposures(eg,dosageandlengthoftreatment)thatwerenotconsistentlyreported,andvariabledefinitionsfor“responsetotreatment”usedbyauthorsacrossstudies.
3.2 | Prophylactic therapy
3.2.1 | Should tricyclic antidepressants (TCAs) be used as prophylactic therapy in adults with CVS?
Potential benefits/harmsFourteen studiesmet inclusion criteria andwere used to inform thisquestion:Theseincluded2randomizedtrialsand12observationalstud‐ies.4‐14Datafromtherandomizedtrialswereconvertedtoasingle‐armcohortofamitriptylinefor inclusion intoasummaryestimateforami‐triptyline's symptomaticeffect.Asummaryestimate fromall includeddatarevealedthatapproximately70%ofpatientswithCVSexhibitedasymptomresponse(variablydefinedforvariabledurations).Sixstudieswere frompediatricpopulations, four studies fromadult populations,andfourstudiesfrommixedadult/pediatricpopulations(seeTable2a,b).Acrossthesestudies,413/600(70%)ofpatientsreportedcompleteorpartialimprovementwithadecreaseinfrequency,duration,orseverityofCVSsymptomswhentreatedwithaTCA,mostcommonlyamitrip‐tyline.Hejazietal.inanopen‐labelstudyof46adultpatientsdemon‐stratednotonlyamarkedreductioninthenumberofCVSepisodesfrom17to3,andinthedurationofaCVSepisodefrom6to2days,butalsoareductioninthenumberofEDvisits/hospitalizationsfrom15to3.3withAT.Ninestudies reportedonadverseevents, themostcommonbeingsedationandweightgain.Bolesetal.2010hadoneofthelarg‐est patient cohorts and noted that 72/139 pediatric patients and 39/54
(72%)adultsexperiencedTCA‐relatedsideeffectsand29/137pediatricpatients and 13/61 (21%) adult patients discontinued amitriptyline be‐causeof sideeffects.7However, adverseevents leading to treatmentdiscontinuation were not systematically reported across the studies.
Certainty of evidenceTheoverallcertaintyoftheevidencewasjudgedtobeverylow.Riskofbiaswasaconcern(lackofcontrolgroupandpossibleselectionbiasintheobservationalstudies,andlackofobviousblindingandaninten‐tiontotreatanalysisintherandomizedtrials).Therewasalsoconcernregarding inconsistency, indirectness (many of the studies includedonlypediatricpatients),andimprecision(forafewoftheoutcomes).
3.2.2 | Should topiramate be used as prophylactic therapy in adults with CVS?
Key messageThere is very low certainty in the evidence that topiramate should be usedasprophylactictherapyinCVS.SeeTable4forfullevidenceprofile
Potential benefits/harmsOnestudymetinclusioncriteriathatinvestigatedtheroleoftopira‐mateinCVS.15Sezeretal.investigatedtheuseoftopiramate(n=16)andpropranolol(n=22) in38pediatricpatientswithCVSinaret‐rospectivecohortstudyinTurkey.Atbaseline,thetopiramategroup(compared to the propranolol group) had significantly fewer epi‐sodesofvomiting/cyclebeforetreatment,fewerattacks/yearaftertreatment, decreased median duration of cycles, and fewer peaknumberofemeses/hourduringanattack.Assuch,patients in thetopiramate group might have been less severe prior to treatment than the propranolol group. Patientswere followed for 1year. Atfollow‐up,responderrates(patientswhohadzeroattacksintheyearfollowing treatmentorpatients that a≥50% reduction in attacks)weresignificantlyhigherinthetopiramategroup15/16(94%)com‐paredtothepropranololgroup18/22(81%).Inthetopiramatearm,81%becameepisodefreeand13%showedatleast≥50%reductioninnumberofepisodes.Per thestudy, the fourpatientswhowerenon‐responsivetopropranololweretreatedwithtopiramate,andallof themhada “satisfactory response,” thoughthiswasnotclearlydefinedby the authors. Theonepatientwhowasnon‐responsivetotopiramatewasalsonon‐responsivetoothermedications,includ‐ingpropranolol, amitriptyline,andcyproheptadine.Oneadditionalstudy reported on topiramate use in adults (Kumar et al.); in this study,18/92adultsweretreatedwithtopiramate,butnotenoughdetailwasprovidedtodiscerntheefficacyoftopiramatealone,aspatients in this cohort also received treatment with amitriptyline and mitochondrial supplements. 12
InthestudybySezeretal.,therewerenodropoutsfromad‐verseevents,andnostatisticallysignificantdifferenceinadverseevents between the propranolol and topiramate groups.15 Two patients experienced drowsiness and dizziness with topiramate,andmeanweightlossaftertheendof12monthswas1.1±0.5kg(2.9%).
a Overall,14studies(includingtheinterventionarmfrom2RCTs)wereincludedinthisanalysis.
b Therewereissuesaroundselectionbias,nointentiontotreatanalysis,confounding,co‐interventionswithmitochondrialsupplements,andvariablefollow‐up.Theoutcomeswerevariablyreported
b Thestudy(Sezer2016)included16pediatricpatients.Overallresponders(≥50%reduction)=94%(partialorcompleteresponse).Inoneadditionalstudy(Kumar2012),17/76adultpatientsreceived
Certainty in effectsTheoverall certainty in theeffectswasvery lowdue toconcernsaboutstudyquality,imprecision(feweventsandsmallsamplesize),and indirectness (the study population was pediatric patients)
3.2.3 | Should aprepitant be used as prophylactic therapy in adults with CVS?
Potential benefits/harmsOneobservationalstudyinvestigatedtheuseofaprepitantbothasabortive therapy and asprophylactic therapy inCVS.16 This study by Cristofori etal., published in 2014, included pediatric patientsandwasretrospectiveindesign,collectingdatafromadministrative,pharmacy, and clinical databases as well as telephone interviewswithparentsofpatients.The41includedpatientsmetNASPGHANcriteria for diagnosis of CVS and had failed or could not toleratepast treatments (Table2a,b). Forty‐one children and adolescentswere included with 25 being administered aprepitant as an abortive medicationand16asprophylaxis.Someadolescents in thisgroupweighed>60kg.Therewasnocontrolgroup.Patientsweregivenan“abortive”regimenofaprepitant if theyhadaprodromalphasethat suggestedan imminentCVSattack.With respect toco‐inter‐ventions,individualswerealsobeingtreatedwithpropranolol9/15(60%),amitriptyline7/15 (46%),coenzymeQ105/15 (33%),andL‐carnitine 3/15 (20%).16
Theoutcomeswerecompleteresponse(noCVSepisodes),par‐tial response (≥50% reduction in both frequency and intensity ofCVSsymptoms),noresponse(<50%reductioninCVSfrequencyandintensity),CVSepisodes/year,hospitaladmissions/year,durationofepisodes, number of vomits/episode, duration of interspersedpe‐riod(days),andpercentageofschoolattendance.Alloutcomes(forabortiveandprophylacticgroups)weremeasuredata12‐monthfol‐low‐up time point.
In theprophylacticgroup,at12‐month follow‐up,19%of in‐dividuals achieved a complete response (3/16) and 62% (10/16) achievedapartialresponse.Overall,82%(13/16)achievedeithercompleteorpartialresponse.Twochildrenfailedtorespond(2/16,19%).
With respect to adverseevents, in theprophylaxis group,onepatient discontinued therapy due to severe migraine (1/16, 6%).Other side effects noted included hiccups (3/16, 19%), asthenia/fatigue (2/16, 12.5%), increased appetite (2/16, 12.5%), and mildheadache(1/16,6%).
Certainty of evidenceThecertaintyintheevidencewasverylowduetoconcernforriskofbias(lackofacontrolpopulation,possibleselectionbiasandcon‐founding).Therewasalsoconcernregardingindirectness,giventhat
the study included a population that failed prior CVS treatments,and was on several concomitant medications. Some adolescents wereatanadultweight(>60kg)intheprophylacticgroupandweredosedaccordingly,makingthislessofaconcern.
3.2.4 | Should zonisamide or levetiracetam be used as prophylactic therapy in adults with CVS?
Potential benefits/harmsOne retrospective study met inclusion criteria.17 Clouse etal. re‐viewedoutpatientrecordsandconductedinterviewsof20adultpa‐tientswithCVSwhohad receivedprophylactic zonisamide (mediandose, 400mg/day) or levetiracetam (median dose, 1000mg/day)whentricyclicantidepressants (TCAs)alonehadfailed,were intoler‐able,orunsuitable.SixteenpatientsweretreatedwithzonisamideandfourwithlevetiracetamforCVSprophylactictherapy.Medianfollow‐upafterinitiationoftheinterventionwas10months.
Outcomesmeasured included episode frequency and change insymptoms.Ascore≥2wasrequiredfora“favorable”clinicalresponse.“Better” as a clinical responsewasnotdefined.The studyused thefollowing Likert scale: 0=no significant improvement or worse;1=slight improvement, requiring treatment changes; 2=moderateimprovement,regimenstablebutsymptomsnotcompletelyresolved;and3=clinicalremissionandcompletepatientsatisfactionwithther‐apy.Twelveoutof16patientsinthezonisamidegroupand3outof4 in the levetiracetamgroup reported a favorable clinical response.Frequencyofvomitingepisodesdecreasedsignificantlyafterinitiationofeitherzonisamideorlevetiracetamfrom1.3to0.5episodes/month.Intotal,18/20(90%)statedthattheywerebetterondrugtherapy(2unchanged,0worse).Therewerenodataonnumberofhospitaliza‐tionsorEDvisits.
Four subjects out of 20 reported “severe” side effects con‐sistingoffatigue,confusion,headache,anddizziness,whichwereeliminatedin3/4ofthesepatientsoncetheyswitchedtotheotherantiepileptic.Twoofthese4patientswerenotedtohaveconcom‐itantuseofTCAs,and1ofthe4patientswasonahighdoseoflevetiracetam (3000mg/day). Five subjects out of 20 reporteddepression,muscleweakness,difficulty sleeping,dizziness,poorconcentration/memory, confusion, or tiredness/fatigue. Onesubjecton levetiracetamdevelopedangioedema,whichresolvedwhen switched to zonisamide. Only one subject out of 20 re‐portedantiepilepticdrugs intolerable inspiteofswitchingdrugsand dosages.
Certainty in the evidenceThecertaintyintheevidencewasverylow.Werateddownforriskofbiasandimprecision(smallsamplesize,raisingconcernaboutop‐timalinformationsize).
a Thiswasaretrospectivecohortstudywithnocontrolpopulationandconcernsaboutpossibleselectionbias.Thestudyincludedcohortswhoreceivedprophylaxisandabortivetreatment.Onlythe
patientswhoreceivedprophylaxisarepresentedhere.
b ThepatientpopulationincludedpediatricpatientsthatfailedpriorCVStreatmentsandwereonseveralconcomitantmedications.
c Sideeffectswerereportedonlyintheprophylacticgroupaffecting5/16,31%:hiccup(3/16,19%),asthenia/fatigue(2/16,12.5%),increasedappetite(2/16,12.5%),mildheadache(1/16,6%),andsevere
a Ascore≥2wasrequiredfora“favorable”clinicalresponse.“Better”asaclinicalresponsewasnotdefined.Likertscale:0=nosignificantimprovementorworse;1=slightimprovement,requiring
b Thisretrospectivestudywasbasedonchartreviewandpatientinterviewswithnocontrolgroupandconcernsforpossibleselectionbias,baselineconfounding,andawarenessoftreatmentwhen
mea
surin
g ou
tcom
e (n
o bl
indi
ng).
c ThispatientpopulationwasadultswhowereunresponsivetoTCAs.
d Werateddownforimprecisionduetothesmallsamplesizeandfewevents.
e Severesideeffects:fatigue,confusion,headache,anddizziness(4/20)whichwereeliminatedin3of4patientsonceantiepilepticwasswitchedtotheother.Moderatesideeffects:depression,muscle
3.2.5 | Should mitochondrial supplements be used as prophylactic therapy in adults with CVS?
Key messageInpatientswithCVS, there isvery lowcertainty intheevidencefortheuseofmitochondrialsupplements,suchasCo‐enzymeQ10,andriboflavinasprophylactictherapy.SeeTable7forfullevidenceprofile.
Potential benefits/harmsTheonly comparative study to evaluate the efficacy ofCoenzymeQ10wasconductedbyBolesetal.(2010).7Inthisstudy,theauthorscomparedtheefficacyofCoenzymeQ10toamitriptylineinpatientswith CVS via an Internet‐based survey that asked subjects abouttheir responsetotreatment.Elevenoutof22subjects,usingvary‐ingdosesofCoenzymeQ10, reporteda50%reduction inepisodefrequency,8/22reporteda50%reductioninepisodeduration,and8/20reporteda50%reductioninnauseaseverity.Outof28partici‐pantsonCoenzymeQ10,nosideeffectswerereported.ThesurveydidnotallowaphysiciantoconfirmifthepatienttrulyhadCVSandwassubjecttorecallandself‐selectionbias.Nopublishedstudiesre‐portedontheefficacyofriboflavininCVSpatients.TheBoles2011study included riboflavinbutdidnot reporton response for thesepatients.
Themajorityof studies that reportedon theuseofmitochon‐drial supplements was not amenable to providing estimates on the efficacyofmitochondrialsupplementsbecausethesewereusedasco‐therapyinconjunctionwithotheragentsorbecauselackofre‐portingofoutcomesspecifictomitochondrialtherapy.7,8,10,12,16,18
Dataon the reportedprevalenceofmitochondrial supplementtherapy as co‐interventions are reviewed below. The Lee etal.(2012)systematicreviewwasnotusedtoinformthisoutcomebe‐cause it either included studies that did not meet our inclusion crite‐riaorincludedstudiesthatasdiscussedbelow,usedsupplementsasco‐therapy.19Kumar2012conductedaretrospectiveanalysisof101patientswhometRomeIIIcriteriaforCVS.Ofthe44/76patientswhoachieveda“completeresponse”withmedicaltherapy,approx‐imately~30%weretakingCo‐enzymeQ10.Ofthosewitha“partialresponse” (21/76) tomedical therapy,35%weretakingCoenzymeQ10.Ofthe11/76patientswith“noresponse”tomedicaltherapy,10%weretakingCoenzymeQ10.
Boles2011conductedaretrospectivestudyinadultandpediat‐ricpopulationswithCVSandreportedonoutcomesofa2‐yearcaseseriesinwhich30patientsweretreatedwithmultipleagents,whichoftenincludedmitochondrialsupplements.Individualeffectfromthemitochondrialsupplementscouldnotbedeterminedfromtheresult,thoughthecombinationofamitriptyline,CoenzymeQ10,andL‐carni‐tinewasusedmostfrequently.TwoarticlesbyHejazietal.describedoutcomesofanopen‐labeledstudyforadultswithCVStreatedwithTCA.10,20Seventeenpercentofthe46patientstookL‐carnitineand/orCoenzymeQ10.ThesecondstudybyHejazireportedoutcomeson132patientsandfocusedoncomparingnon‐respondersandrespond‐ers toTCAtherapy.Thisstudyalsohad17%ofpatientsonL‐carni‐tine/Co‐enzymeQ10.Thereseemedtobeanoverlap in thepatient TA
populationbetweenbothof these studies.With respect toadverseeffects,intheBoles2010study,therewerenoreportedsideeffects(0/20).
Certainty of evidenceThe certainty in the evidence was deemed to be very low due to concernsaboutstudyquality, indirectness,and imprecision (retro‐spectivedesign,lackofacontrolpopulation,probableselectionbias,pediatricpopulation,smallsamplesize,andconfounding).Nopooledeffectestimateorrangeofeffectscouldbecalculated.
3.3 | Abortive medications
3.3.1 | Should triptans be used as abortive therapy in adults with CVS?
Key messageThereismoderatecertaintyintheevidencefortheuseoftriptansas abortive therapy in CVS, primarily based on indirect data. SeeTable8forfullevidenceprofile.
Potential benefits/harmsWe identified four studies thatmet inclusion criteria and that re‐ported on the use of triptans as abortive therapy in CVS. Onesystematic review of treatments for CVSwas not included belowbecause itonlyreviewedtheHikita2011study.21Weadditionallylookedforindirectevidenceinthemigraineliteraturetohelpinformoutcomes,suchasnauseaandvomiting.22
Kumar2012conductedaretrospectivereviewofadultandpe‐diatricpatientsseenattheMedicalCollegeofWisconsinwhometRome III criteria for CVS.12 Data were collected on 101 patients through chart review and patient questionnaires. Response data werenotavailableonallpatients,thoughitwasnotedthattriptanmedications“aborted”CVSepisodesin64/77(83%)ofpatients.
Hikita2011studiedoneadultandelevenpediatricpatients ina prospective cohort study that took place at Teikyo UniversityHospitalinJapan.21PatientshadbeendiagnosedwithsevereCVSby a pediatric neurologist per the International Classification ofHeadacheDisorders.Patientsweregivensumatriptan,aseitherasubcutaneous injection or a nasal spray; the average dose admin‐isteredwasnotspecified.Measuredoutcomesincluded“completeresponse”(novomitingaftertreatment),“effectiveresponse”(vom‐iting frequency reduced by≥50%), or “non‐effective response”(the treatmentwas not effective in preventing vomiting). For the11patientsreceivingsubcutaneoussumatriptaninjection,4/11hadcompleteresolution,5/11hadeffectiveresponse,and2/11hadanon‐effective response. Patients with a family history migraineweremorelikelytorespond(“complete”and“effective”).Amongthefivepatientswhoreceivednasalspray,1/5hadcompleteresolution,1/5hadeffectiveresponse,and3/5hadnon‐effectiveresponse.
Li 1999published a retrospective cohort study in of 214 chil‐drenfromColumbusChildren'sHospitalwithaclinicaldiagnosisofCVS.23Thepurposeofthestudywastodescriptivelycomparethe
characteristicsofthosewithmigraine‐associatedCVSversusthosewithnon–migraine‐associatedCVS.ThediagnosisofCVSwasmadeasaclinicaldiagnosisby treatingclinicians.Median follow‐upwas17.5 months. Measured outcomes included demographic charac‐teristics,vomitingpattern,associatedsymptoms,triggeringevents,andmedicationresponse.Themigraine‐associatedCVSgroup(witheitherselforfamilyhistoryofmigraines)comparedtonon–migraine‐associatedCVS had fewer emeses/episode,more abdominal pain,andmore triggering events for theirCVSepisodes. Li etal. foundthat 24/35 (69%) of children had improvement in symptoms (de‐finedasa≥50%reductioninvomitingepisodes)withsubcutaneoussumatriptan.
Indirect estimates for the effect of sumatriptan on symptomreduction (nausea and vomiting) were derived from the migraineheadache literature.22 In a systematic reviewof patientswithmi‐graineheadaches,butnotnecessarilyCVS,of8randomizedcontroltrials, 45% to 76%of individualswithmigraine headaches experi‐enced a reduction in nausea symptoms within 2 hours with triptans andhigherratesofsymptomimprovementwereseeninindividualsreceiving sumatriptan by either intranasal (50%‐60% range) and sub‐cutaneous routes (76%).22
Amongthe3studiesthatincludeddataontheuseoftriptansas abortive therapy in CVS, no adverse events were reported.12,23Furthermore,nodataonadverseeventsleadingtotreatmentdiscontinuationwere provided in theDerry etal. Cochrane sys‐tematicreview.Adverseeffectsweregenerallydescribedasmildor moderate and self‐limited. No cardiovascular problems werenoted.
Certainty in the evidenceIndirectestimatesinfluencedthecertaintyoftheevidencesupportingtheutilityoftriptansasabortivetherapyinCVS.Withregardtotheoutcome of relief of nausea at 2hours,we hadmoderate certaintyinthebeneficialeffectoftriptans,aspresentedbythesummaryes‐timateyielded fromameta‐analysisofeightRCTs.Wedowngradedforindirectnessasthepopulationstudiedwaspatientswithmigraineheadaches(CVSisinthesubgroupofperiodicsyndromesthatincludemigraine and its equivalents).
With regard to the outcome of treatment response and ad‐verse events (across the three studies in CVS patients), thecertaintyintheevidencewasdeemedtobeverylow.Wedown‐graded due to risk of selection bias, imprecision (concern forfragilityintheestimateduetosuboptimalinformationsize),andindirectness,becausesomestudieswereconducted inpediatricpopulationsandsomedatacomefromaCVS–migraine‐associated phenotype.
3.3.2 | Should 5‐HT3 antagonists be used as abortive therapy in adults with CVS?
a Theobservationalstudieswereatriskforselectionbias.
b Theoutcomewasvariablydefinedacrossstudies:“medicationresponse”or“benefit”whichmayrepresentcomplete/partialresponseorsymptomimprovement.Lietal.foundthat69%ofkids(24/35)
c Somestudieswereconductedinpediatricpopulations,andsomedatacomefromaCVS–migraine‐associatedphenotype.
d Werateddownforimprecisionduetothesmallsamplesizeandfewevents.
e AnoverviewofSRswasusedtoprovideindirectevidencetosupporttheuseoftriptansfornauseaandvomiting.These8studieswereconductedinindividualswithmigraineheadaches,andnausea
. f TheHikita2011studyincluded1adultand11pediatricpatients.
g NodataonadverseeventsleadingtotreatmentdiscontinuationwereprovidedintheDerryetal.SR.AEsweregenerallydescribedasmildormoderateandself‐limited.Nocardiovascularproblems
a Thiswasaretrospectivecohortstudywithnocontrolpopulationandconcernsaboutpossibleselectionbias.Thestudyincludedcohortswhoreceivedprophylaxisandabortivetreatment.Onlythe
patie
nts
who
rece
ived
abo
rtiv
e th
erap
y ar
e pr
esen
ted
here
. b ThepatientpopulationincludedpediatricpatientsthatfailedpriorCVStreatmentsandwereonseveralconcomitantmedications.
28 of 29 | SHARAF et Al.
3.3.3 | Should aprepitant be used as abortive therapy in adults with CVS?
Key messageInpatientswithCVS,thereisverylowcertaintyintheevidencefortheuseofaprepitantasabortive therapy.SeeTable9 for fullevi‐denceprofile
Potential benefits/harmsOneobservational study investigated theuseofaprepitantasabor‐tive therapy andasprophylactictherapyinCVS.16 The study included pediatric patients and was retrospective in design, collecting datafromadministrative,pharmacy, andclinicaldatabases aswell as tel‐ephone interviews with patients’ parents (see section on aprepitant as prophylactictherapyinCVSformoredetails). Intheabortivegroup,ata12‐monthfollow‐uptimepoint,12%(3/25)achievedacompleteresponseand64%(16/25)achievedapartialresponse.Overall,76%(19/25)achievedeitheracompleteorpartialresponse.Sixchildrenhadnoresponse(6/25,24%).Itwasdifficulttodiscernhowoftenpatientsreceived the medication in the abortive group. There were no noted adverseeventsfromaprepitantadministrationintheabortivegroup.
Certainty in the evidenceThe certainty in the evidence was deemed to be very low, forthesamereasonsdiscussed intheprophylacticgroup.Certaintywas reducedby riskof bias (lackof a control population, possi‐bleselectionbias,andconfounding).Therewasalsoconcernre‐garding indirectness,given that thestudy includedapopulationthatfailedpriorCVStreatments,andwasonseveralconcomitantmedications.
3.3.4 | Should we screen for and treat co‐morbid conditions, such as anxiety, depression, migraine headache, autonomic dysfunction, sleep disorders, and substance use in adults with CVS?
Three recommendations (recommendations 7, 9, and 10) thatare presented in the accompanying manuscript were deemed consensus recommendations and no GRADE evidence profile
was created. Recommendation 7 addresses the role of 5‐HT3antagonists, such as ondansetron, as abortive therapy for CVS.Acknowledgingthelackofdirectevidencetoinformthisclinicalquestion, thecommitteereliedon indirectevidenceontheeffi‐cacyofondansetroninpatientswithchemotherapy‐inducednau‐seaandvomiting(CINV)andpostoperativenauseaandvomiting(PONV) in treating acute, delayed, and anticipatory nausea andvomitingtoinformtherecommendation.Forrecommendations9and 10, therewas insufficient evidence in the published litera‐tureexaminingtheroleofscreeningandtreatmentofco‐morbidconditionsonCVSsymptomsandtheeffectsofcomplementarytherapiesonCVSsymptoms.Forthesetworecommendations,thecommittee made consensus‐based recommendations based on their largecollectiveexperienceofmanagingadultandpediatricCVSpatientsandtheirobservationsinclinicalpracticeaswellastherecognitionthatthetreatmentofCVS,afunctionaldisorder,shouldbebasedonabiopsychosocialcaremodel,integratinglife‐stylemodification,prophylactic,and/orabortivemedications,andevidenced‐based psychotherapy to address psychiatric co‐mor‐bidity. Finally, the guideline also includes consensus statementsthat address the diagnosis andworkup of CVS patients as wellasanarrative reviewandsampleprotocol for treatmentofCVSpatientsintheED.
4 | CONCLUSIONS
This evidence review is based on theGRADE framework andwasdeveloped to informtheclinicalpracticeguideline for themanage‐mentofCVS,whichshouldultimatelyimprovepatientoutcomesandreducemorbidityassociatedwiththischronicandoften,debilitatingillness.
None of the authors had any competing interests. Full disclo‐sure statement included. Dr. Sharaf was supported by AcademyHealthDSSF,NYStateECRIPAward,NCIK07CA216326andNCIR01CA211723. Dr. Sharaf is a paid consultant for the non‐profitInstituteforClinicalandEconomicReview,Boston,Massachusetts.Dr.Sultanhasnofinancialdisclosures.
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How to cite this article:SharafRN,VenkatesanT,ShahR,etal.Managementofcyclicvomitingsyndromeinadults:Evidencereview. Neurogastroenterol Motil. 2019;31(Suppl. 2):e13605.