management of cyclic vomiting syndrome in adults: evidence

Neurogastroenterology & Motility. 2019;31(Suppl. 2):e13605. | 1 of 29https://doi.org/10.1111/nmo.13605

wileyonlinelibrary.com/journal/nmo

Received:06March2019 | Revised:01April2019 | Accepted:02April2019DOI: 10.1111/nmo.13605

R E V I E W A R T I C L E

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

*These authors contributed equally.

Abbreviations:AE,adverseevent;CI,confidenceinterval;GRADE,GradingofRecommendationsAssessment,Development,andEvaluation;LR,likelihoodratio;OR,oddsratio;PICO,population,intervention,comparator,andoutcome;RCT,randomizedcontroltrial;RR,relativerisk.

1DivisionofGastroenterology,DepartmentofMedicine,WeillCornellMedicalCenter,NewYork,NewYork2DivisionofGastroenterology,DepartmentofMedicine,MedicalCollegeofWisconsin,Milwaukee,Wisconsin3DivisionofGastroenterologyandLiverDisease,DepartmentofInternalMedicine,CaseWesternReserveUniversitySchoolofMedicine,Cleveland,Ohio4DepartmentofMedicine,DivisionofGastroenterology,Hepatology,andNutrition,UniversityofPittsburghMedicalCenter,Pittsburg,Pennsylvania5DepartmentofPsychiatryandBehavioralSciences,NorthwesternFeinbergUniversitySchoolofMedicine,Chicago,Illinois6DepartmentofNeurologyandNeurologicalSciences,StanfordUniversityMedicalCenter,Stanford,California7DivisionofGastroenterology,DepartmentofMedicine,UniversityofMichiganMedicalSchool,AnnArbor,Michigan8DivisionofPediatricGastroenterology,DepartmentofPediatrics,McMasterUniversity,Hamilton,Ontario9Founder/PresidentEmerita,CyclicVomitingSyndromeAssociation10DivisionofGastroenterology,DepartmentofInternalMedicine,TexasTechUniversityHealthSciencesCenter,Lubbock,Texas11LaneMedicalLibrary,StanfordUniversity,Stanford,California

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.

K E Y W O R D S

cyclicvomiting,technicalreview,treatment

ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttribution‐NonCommercial‐NoDerivsLicense,whichpermitsuseanddistributioninanymedium,providedtheoriginalworkisproperlycited,theuseisnon‐commercialandnomodificationsoradaptationsaremade.©2019TheAuthors.Neurogastroenterology & MotilityPublishedbyJohnWiley&SonsLtd

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2 of 29 | SHARAF et Al.

1 | INTRODUC TION

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.).

12DivisionofPediatricGastroenterology,HepatologyandNutrition,DepartmentofPediatrics,MedicalCollegeofWisconsin,Milwaukee,Wisconsin13DivisionofGastroenterology,DepartmentofMedicine,UniversityofMinnesota,MinneapolisVeteransAffairsHealthcareSystem,Minneapolis,Minnesota

CorrespondenceRaviN.Sharaf,WeillCornellMedicalCenter,JayMonahanCenterforGastrointestinalHealth,NewYork,NY.Email:[email protected]

Funding informationThisworkwasfundedbytheCyclicVomitingSyndromeAssociation(CVSA),anon‐profitorganizationforpatientswithCVSandtheircaregivers.

mailto:[email protected]

| 3 of 29SHARAF et Al.

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

thelimitedtotalliterature,asinglesearchwasconductedforallPICOQuestions.

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.

TA B L E 1 PICOquestions

PICO questions

MethodPopulation Intervention(s) Comparator Outcomes

Prophylactictherapy

AdultswithCVS

1.TCAs2. Topiramate 3. Zonisamide Levetiracetam4.Aprepitant5. Mitochondrial supplements CoQ10,L‐CarnitineRiboflavin

Placeboorusual care

1.Completeresponseorpartialresponseorsubjectiveimprovement(reductioninfrequencyordurationorseverityofCVSsymptoms)2.DecreaseinfrequencyordurationorseverityofCVSattacks(ifreportedseparately)3.ReductioninnumbersofhospitalizationsofEDvisits

per year 4.Adverseeffects—%ofpatientsdiscontinuingtreatment

GRADE

Abortivetherapy

AdultswithCVS

6. Triptans 7.5HT3antagonists

Ondansetron 8.Aprepitant

Placeboorusual care

1.Completeresponseorpartialresponseorsubjectiveimprovement(reductioninfrequencyordurationorseverityofCVSsymptoms)2.DecreaseinfrequencyordurationorseverityofCVSattacks(ifreportedseparately)3.ReductioninnumbersofhospitalizationsofEDvisits

per year 4.Adverseeffects—%ofpatientsdiscontinuingtreatment

GRADEandnarrative review

F I G U R E 1 PRISMAflowdiagram


TAB

LE 2

Characteristicsofincludedstudies

(a)

Aut

hor/

year

Med

icat

ions

Abo

rtiv

e vs

. Pr

ophy

lact

ic

trea

tmen

tA

dult

or

pedi

atric

Stud

y de

sign

Coun

try

N (#

pat

ient

s for

w

hich

med

icat

ion

data

repo

rted

)Po

pula

tion

char

acte

ristic

sD

urat

ion

of

follo

w‐u

p

1Badihian

et a

l. (2

018)

Amitriptyline:0.5mg/kg,

increasedto1mg/kgafter

1week

OR

Cyproheptadine:0.1mg/kg,

increasedto0.2mg/kgafter

1weekMedicationswere

deliveredtopatientat2‐week

inte

rval

s.

Prophylactic

Pediatric

Randomizedtrialof

amitr

ipty

line

vs

cypr

ohep

tadi

ne.

MD

vis

its e

very

2weeksover

6 m

onth

s

Iran

70eligible,64

randomized(32/

arm),0lostto

follow‐up

DiagnosisofCVS(basedonRomeIII

crite

ria).

3‐

15 y

ears

old

. 2 tr

eatm

ent g

roup

s no

t statisticallydifferent

6 m

onth

s

2Sh

eare

r et

al.

(201

6)

Amitriptyline(median45mg,

rang

e 10

‐140

mg)

Prophylactic

Adults

Retr

ospe

ctiv

e

coho

rtUnited

Kin

gdom

14 p

atie

nts

on

amitr

ipty

line.

DiagnosisofCVSbasedon“symptoms

compatiblewithCVS.”

Meanage~30years

1‐5

year

s

3Hikitaetal.

(201

6)Valproicacid

Valproicacidwithphenobarbital

PhenobarbitalAmitriptyline

PhenytoinCarbamazepine

CyproheptadinePrimidone

Propranolol

Clonidinehydrochloride

(Dosagesnotspecifiedforall

med

icat

ions

)

Prophylactic

Pediatric

Retr

ospe

ctiv

e

coho

rtJapan

18 re

ceiv

ed

prop

hyla

ctic

m

edic

atio

ns

CVSdiagnosisbasedonInternational

ClassificationofHeadacheDisorders

crite

ria

5 ye

ars

4Sezeretal.

(201

6)To

pira

mat

e (s

tart

ed a

t 25

mg

at

night.Increasedtoamaximum

of75mg/dayifneeded.

OR

Propranolol(startedat1mg/kg/

day,increasedafter1monthif

needed,goal1.4mg/kg/day)

Prophylactic

Pediatric

Retr

ospe

ctiv

e ch

art r

evie

w a

nd

patie

nt

ques

tionn

aire

.

Turkey

38 (1

6 pa

tient

s on

to

pira

mat

e an

d 22

pa

tient

s on

pr

opra

nolo

l)

CVSdiagnosedbyRomeIIIcriteriaand

InternationalHeadacheSociety

Classification.

Topiramatevs.Propranololgrouphad

significantly:Lessepisodesofvomiting/

cyclebeforetreatmentFewerattack

numbers/yr.aftertreatmentFewer

mediandurationofcyclesinhourFewer

peaknumberofemesesperhour

Atleast

12 m

onth

s

5Jensen

et a

l. (2

015)

Tric

yclic

ant

idep

ress

ants

Phenergan

Ond

anse

tron

L‐Carnitine

Co‐Q10

Show

ers

Mar

ijuan

a (D

osag

es n

ot d

escr

ibed

)

Abortiveand

prop

hyla

ctic

Adults

Cross‐sectional.

Phenomenological

appr

oach

.

USA

16DiagnosticcriteriaforCVSnotmentioned.

Medianageatdiagnosis25years.Patients

withCVSrecruitedfromCyclicVomiting

SyndromeAssociationWebsite,Facebook

page,andnewsletter.Surveyand

qualitativeinterviewsofpatientswithCVS

Cross‐sectional

so s

ingl

e tim

e po

int (Continues)


(a)

Aut

hor/

year

Med

icat

ions

Abo

rtiv

e vs

. Pr

ophy

lact

ic

trea

tmen

tA

dult

or

pedi

atric

Stud

y de

sign

Coun

try

N (#

pat

ient

s for

w

hich

med

icat

ion

data

repo

rted

)Po

pula

tion

char

acte

ristic

sD

urat

ion

of

follo

w‐u

p

6M

oses

et a

l. (2

014)

Amitriptylinewasstartedatadose

of0.2mg/kgperday,oncedaily

at b

edtim

e an

d in

crea

sed

as

clin

ical

ly in

dica

ted

and

tole

rate

d by

the

patie

nt.

Cyproheptadinewasstartedat

0.25‐0.5mg/kgoncedailyat

bedtimeand“infrequently”

divi

ded

twic

e a

day.

O

ndan

setr

on: T

he d

ose

used

was

0.3mg/kgperdoseevery6hours

asneededforcontinuedvomiting

or n

ause

a.

Abortiveand

prop

hyla

ctic

Pediatric

Retr

ospe

ctiv

e

coho

rtUSA

106

CVSdiagnosisbasedonRomeIIIcriteria:

Personalhistoryofmigrainewas

reportedin25%ofthechildrenanda

familyhistoryofmigrainein72%

Notspecified

7Tr

eepo

ng‐

karuna

et a

l. (2

014)

AmitriptylinePropranolol

CyproheptadineSodium

valp

roat

e (Medicationdosagesnotexplicitly

stat

ed b

ut p

rior c

linic

al p

ract

ice

guidelinesreferencedfor

dosa

ges)

Prophylactic

Pediatric

Retr

ospe

ctiv

e

coho

rtTh

aila

nd

29 p

atie

nts r

ecei

ved

eith

er p

ropr

anol

ol

(n=11),cyprohepta‐

dine(n=4),and

amitr

ipty

line

(n =

14)

. Long‐termoutcomes

wer

e av

aila

ble

in 1

9 pa

tient

s.

Age(mean±std.)11.3±4.9years

3 m

onth

s to

5

year

s

8Cristofori

et a

l. (2

014)

Aprepitant

Abortive:125mginearlyprodrome,

thenifneeded:a)If<15kg,80mg

(Day1),40mg(Days2/3);b)if

15‐20kg,80mg(Days1/2/3),c)

if>20kg,80mg(Days2/3).

Prophylactic(twice/week):40mg

if<40kg,80mgif41‐59kg,

125mgif>60kg

Abortiveregimenofaprepitant

givenifprodromalphase*

suggestedimminentCVSattack.

Otherwise,prophylacticaprepitant

dosegiven.Alloraladministration.

*Prodromalphase=symptomssuch

asnausea,anorexia,changein

mood,anxiety,dizzinessand

auto

nom

ic sy

mpt

oms *

Som

e children>60kg

Abortiveand

prop

hyla

ctic

Pediatric

Retr

ospe

ctiv

e co

hort

United

Kin

gdom

41 to

tal 1

6 pr

ophy

lact

ic

(thou

gh o

utco

me

data

onl

y co

llect

ed

on 1

5). 2

5 ab

ortiv

e

MetNASPGHANcriteriaforCVS.Alleither

failedorcouldnottoleratepriortreatment.

Nostatisticallysignificantdifferences

betweenabortive/prophylaxisgroups

exceptthatabortivegrouphadahigher

rateofprodromalevents(21/25vs3/15).

Currenttreatmentforabortivegroup

Propranolol(0.5‐1mg/kg/day):13/25(52%)

Amitriptyline(1‐1.5mg/kg/day):10/25(40%)

Co‐EnzymeQ10(10mg/kg/day):6/25(24%)

L‐Carnitine(100mg/kg/day):4/25(16%)

Currenttreatmentforprophylaxisgroup:

Propranolol(0.5‐1mg/kg/day):9/15(60%)

Amitriptyline(1‐1.5mg/kg/day):7/15(46%)

Co‐EnzymeQ10(10mg/kg/day):5/15(33%)

L‐Carnitine(100mg/kg/day):3/15(20%)

Abortive:median

30months,

rang

e 16

‐60

mon

ths

Prophylactic:

med

ian

24months,

rang

e 18

‐60

mon

ths

TAB

LE 2

(Continued)

(Continues)


(a)

Aut

hor/

year

Med

icat

ions

Abo

rtiv

e vs

. Pr

ophy

lact

ic

trea

tmen

tA

dult

or

pedi

atric

Stud

y de

sign

Coun

try

N (#

pat

ient

s for

w

hich

med

icat

ion

data

repo

rted

)Po

pula

tion

char

acte

ristic

sD

urat

ion

of

follo

w‐u

p

9Ku

mar

et a

l. (2

012)

Abortive

Triptans(dosenotmentioned)Hot

show

ers Prophylactic

Tricyclicantidepressants(TCAs,goal

1mg/kg/day

Topi

ram

ate

(dos

e no

t men

tione

d)

Mitochondrialtherapy:(Carnitine1

gramtwicedaily,Co‐enzymeQ‐10

200mgtwicedaily,riboflavin

100

mg

once

dai

ly)

Abortiveand

prop

hyla

ctic

Adult

Retr

ospe

ctiv

e ch

art r

evie

w p

lus

“prospective”

standardized

ques

tionn

aire

.

USA

101.Follow‐up

avai

labl

e in

76

/101

(75%

) on

med

ical

ther

apy.

MetRomeIIICriteriaforCVS.Meanage

27 y

ears

Anxiety(47%)

Dep

ress

ion

(49%

) Dys

auto

nom

ia (6

4%)

30/70(43%)personalhistoryofmigraine

41/64(64%)hadafamilyhistoryof

mig

rain

e

Meandurationof

follow‐upwas

11.2±6.2

mon

ths.

10Leeetal.

(201

2)TCAPropranolol

L‐carnitineandamitriptyline

Erythromycin

CoenzymeQ

PhenobarbitalValproate

Pizotifen

Cyproheptadine

L‐Carnitine

Sum

atrip

tan

Zonisamide/Levetiracetam

Abortiveand

prop

hyla

ctic

Adultand

pedi

atric

Syst

emat

ic re

view

. N

ot

appl

icab

le1

pros

pect

ive

coho

rt s

tudy

24

retr

ospe

ctiv

e co

hort

stu

dies

. 1093patients,of

who

m 3

77 w

ere

adul

ts

LiteraturesearchMEDLINEviaOvid

(January1948toOctober2011)and

EMBASE(January1980toOctober

2011).Referencessearchedaswell.Case

reportsexcluded.

CVSdiagnosisbasedonRomeIIIcriteria.

AdultCVSpatients(vspediatric)hada

significantlyhigherfamilyhistoryof

head

ache

/mig

rain

e (5

6% v

s 28

%

(P =

0.0

06))

Not

repo

rted

11Bolesetal.

(201

1)*Dietary:“3+3diet”(3mealsand3

snacksadayincludingbetween

mealsandatbed‐time),andthe

avoidanceoffasting.

•Co‐enzymeQ10:Maximumblood

level>3.0mg/L

•L‐carnitine:Maximumbloodlevel>

40 m

icrom

olar

•Amitriptyline/Nortriptyline:

Maximumbloodlevel>150ng/ml

•Cyproheptadine:Maximumdosage

of0.5mg/kg/day

•Topiramate:Maximumdosageof

200

mg

twic

e a

day

(in a

dole

s‐centsandadults).Usedasalast

reso

rt m

edic

atio

n

Dosageswereincreaseduntiloneof

thefollowingoccurred:

•Resolutionofvomitingepisodes

•Intolerablesideeffectsthatfaileda

reductionindosagefollowedbya

slow

dos

age

incr

ease

Abortiveand

prop

hyla

ctic

Adultand

pedi

atric

Retr

ospe

ctiv

e co

hort

USA

42 m

et in

clus

ion

criteria,data

avai

labl

e on

30

patie

nts

CVSdiagnosesbasedonICD‐9and

NASPGHANandRomeIIIcriteria.

Age:3‐26years(median12).Theageof

onsetofvomitingepisodeswas1week

to15years,withamedianof4years.

Of42patients,74%withchronicpain,

74%withGIdysmotility,57%with

“functionalorautonomic‐related

conditions,”31%withmentalhealth

disorders,36%with“cognitive

disorders”

Min

imum

2

year

s

TAB

LE 2

(Continued)

(Continues)


(a)

Aut

hor/

year

Med

icat

ions

Abo

rtiv

e vs

. Pr

ophy

lact

ic

trea

tmen

tA

dult

or

pedi

atric

Stud

y de

sign

Coun

try

N (#

pat

ient

s for

w

hich

med

icat

ion

data

repo

rted

)Po

pula

tion

char

acte

ristic

sD

urat

ion

of

follo

w‐u

p

12Hikitaetal.

(201

1)Su

mat

ripta

n su

bcut

aneo

us

injection(agex4+20)/

(100x3mgornasalsprayversus

nasa

l spr

ay (2

0 m

g)

Abortive

Adultand

pedi

atric

Prospective

non‐randomized

tria

l

Japan

12 p

atie

nts

enro

lled;

11

chi

ldre

n an

d 1

adul

t

DiagnosedwithCVSbyInternational

ClassificationofHeadacheDisorders.

Familyhistorymigraineinafirst‐degree

relativein33%(4of12)patients.

Not

app

licab

le

13Bolesetal.

(201

0)Amitriptyline(ranged

from<0.5mg/kg/day),medium,

andhigh(≥1.0mg/kg/day)

CoenzymeQ‐10:(ranged

from≥10mg/kg/day

or≥300mginapatient≥30kg)

Prophylactic

Adultand

pedi

atric

Childand

adol

esce

nt

data

co

mbi

ned

to c

reat

e a

“pediatric‐

onset”

grou

p.

Retr

ospe

ctiv

e co

hort

N

ot

appl

icab

leAmitriptyline:249

subjectsCo‐en

‐zymeQ10:32

subj

ects

PatientsmetRomeIIIandNASPGHAN

forCVS.Recruitmentvianewsletters,

theCyclicVomitingSyndrome

AssociationWebsite,emailsto

mem

bers

and

ass

ocia

ted

phys

icia

ns.

Cross‐sectional

stud

y (n

o follow‐up

avai

labl

e)

14Hejazietal.

(201

0)Tr

icyc

lic a

ntid

epre

ssan

ts

(amitriptyline,nortriptyline,or

doxepin,startedat10to25mg,

goal1mg/kg.Actualdoses

achievedwere0.25to3mg/kg

(rang

e: 1

5 to

200

mg/

daily

; av

erag

e do

se 1

00 m

g at

be

dtim

e).

Prophylactic

Adult

Open‐Label

Prospectivecohort

Officevisits,

tele

phon

e interviews,and

ques

tionn

aire

s at

timezeroandevery

6‐m

onth

inte

rval

s.

USA

41AllmettheRomeIIIcriteriaforCVS12pts

had

mig

rain

e he

adac

hes.

3 pt

s had

a

familyhistoryofmigraine22/46(53%)

curr

ent/

past

mar

ijuan

a us

e.

InadditiontoTCAs,7patientson

L‐carnitine/CoQ10,3patientson

topiramate,buttreatmenteffectfrom

thes

e m

edic

atio

ns w

as n

ot re

port

ed.

Upto2years

15Haghihat

et a

l. (2

007)

Amitriptyline(1mg/kgperday)

OR

Propranolol(1mg/kgperday)

Prophylactic

Pediatric

Randomizedtrialof

amitr

ipty

line

vs

prop

rano

lol

Iran

164

patie

nts

(81

on

prop

rano

lol a

nd 8

3 on

am

itrip

tylin

e)

CVSdiagnosis:>/=3episodesof

intractable,self‐limited,non‐bilious

vomiting,separatedbysymptom‐free

inte

rval

s.

8/164(5%)historyofseizures(on

antic

onvu

lsant

s)

90/1

64 (5

5%) o

lder

chi

ldre

n w

ith

recurrentheadaches;in20%,symptoms

weretypicalofmigraine.

39/164(24%):familyhistorymigraine

6 m

onth

s to

12

yea

rs

16N

amin

et a

l. (2

007)

Amitriptyline(targetdoseof

1mg/kg/dayover1‐2months.

Mea

n da

ily d

ose

75 m

g (ra

nge

50‐1

50 m

g)

Prophylactic

Adults

Sing

le‐a

rm c

ohor

t study,prospective.

Thiscohortof

patie

nts w

as

stud

ied

in a

2‐y

ear

follow‐up

prog

ram

.

USA

31 e

ligib

le. 2

7 re

ceiv

ed a

mitr

ipty

‐line,24onitforat

leas

t 3 m

onth

s. 1

5 patientsonitforat

leas

t 12

mon

ths.

RomeIIIcriteriaforCVSTheHamilton

RatingScaleforAnxiety:84%hadan

anxietydisorderZungDepression

Inventory:78%sufferedfrommild‐to‐

seve

re d

epre

ssio

n.

4/31(13%)patientsreportedmigraine,

14/31(45%)hadafamilyhistoryof

mig

rain

e.

2 ye

ars

TAB

LE 2

(Continued)

(Continues)


(a)

Aut

hor/

year

Med

icat

ions

Abo

rtiv

e vs

. Pr

ophy

lact

ic

trea

tmen

tA

dult

or

pedi

atric

Stud

y de

sign

Coun

try

N (#

pat

ient

s for

w

hich

med

icat

ion

data

repo

rted

)Po

pula

tion

char

acte

ristic

sD

urat

ion

of

follo

w‐u

p

17Clouse

et a

l. (2

007)

Zonisamide(mediandose,

400

mg/

d)

Levetiracetam(mediandose,

1000

mg/

d)

Prophylactic

Adults

Retr

ospe

ctiv

e ch

art r

evie

w a

nd

patie

nt in

terv

iew

USA

20 (1

6 on

Zonisamide,4on

Levetiracetam)

CVSdiagnosis:>/=3discretestereotypi

‐calepisodesofseverevomiting

separatedbysymptom‐freeintervalsof

atleast2weekswithnostructuralor

metabolicexplanationforthesubjects.

Allpatientswhohadfailedorcouldnot

tole

rate

tric

yclic

ant

idep

ress

ant

mon

othe

rapy

Meanage38.5±3.2years,18White,10

mal

es

Meanof9.5±

1.8

mon

ths

18Bolesetal.

(200

6)Abortive

IVdextroseOndansetron

LorazepamPromethazine

Sum

atrip

tan

Prophylactic

AmitriptylineCyproheptadine

Propranolol

(Dos

ages

not

list

ed)

Abortiveand

prop

hyla

ctic

Adultand

pedi

atric

Cross‐sectional

stud

y vi

a cl

inic

al

ques

tionn

aire

. Ra

ndom

recruitmentfrom

CyclicVomiting

Synd

rom

e Association,USA/

Canada.

USAand

Canada

23CVSplus(CVS+

neur

omus

cula

r di

seas

e)

44CVSminus(no

neur

omus

cula

r di

seas

e)

13 s

ubje

cts

with

CVSthatwerenot

subg

roup

ed

CVSplusgrouphadearlierageofonset

ofsymptoms.

DefinitionofCVSnotexplicitlyspecified.

Cross‐sectional

(nofollow‐up

avai

labl

e)

19Aanpreung

et a

l. (2

002)

Amitriptyline

Pizotifen

Propranolol

Dosagenotspecified

Prophylactic

Pediatric

Retr

ospe

ctiv

e co

hort

Sirir

aj

Hospital,

Thai

land

25CVSdiagnosis:>/=3discrete,stereotypic

episodesofnauseaandvomiting;

each>12hours;morethan7days

betw

een

epis

odes

; and

no

stru

ctur

al o

r metabolicexplanationforthe

sym

ptom

s.

6/25withheadaches(ofthese3had

familyhistoryofmigraine)

Patientswereon

medicationsfor

at le

ast

3 m

onth

s

20Prakash

et a

l. (1

999)

Amitriptyline

Doxepin

Nor

trip

tylin

e D

esip

ram

ine

Imip

ram

ine

Prophylactic

Adults

Retr

ospe

ctiv

e chartreview.Had

com

paris

on g

roup

(functional

naus

ea/

abdo

min

al p

ain)

USA

17

CVSdefinition:a)>/=3discrete,

stereotypicepisodesofnauseaand

vomiting,eachlasting12hours;b)

7 da

ys b

etw

een

epis

odes

; c) c

ompl

ete

resolutionofsymptomsbetween

epis

odes

; and

d) n

o st

ruct

ural

or

metabolicexplanationforthe

sym

ptom

s.

4 pa

tient

s w

ith m

igra

ine

head

ache

.

23±7months

TAB

LE 2

(Continued)

(Continues)


(a)

Aut

hor/

year

Med

icat

ions

Abo

rtiv

e vs

. Pr

ophy

lact

ic

trea

tmen

tA

dult

or

pedi

atric

Stud

y de

sign

Coun

try

N (#

pat

ient

s for

w

hich

med

icat

ion

data

repo

rted

)Po

pula

tion

char

acte

ristic

sD

urat

ion

of

follo

w‐u

p

21Lietal.

(199

9)Su

ppor

tive

ther

apy

IVhydration

Antiemetic/Prokinetictherapy

Phenothiazines

ProkineticAgents

Ond

anse

tron

Antimigrainetherapies

Propranolol

Cyproheptadine

AmitriptylineSumatriptan

(Dos

ages

not

des

crib

ed)

Abortiveand

prop

hyla

ctic

Pediatric

Retr

ospe

ctiv

e ch

art r

evie

w a

nd

stru

ctur

ed

inte

rvie

ws

USA

214

CVSdiagnosismadebasedonclinical

judg

men

t.

176/214(82%)Migraine‐relatedCVS

(familyhistoryofmigraines,subsequent

developmentofmigraines)

38/214(18%)Non–migraine‐relatedCVS

Med

ian

follow‐up

17.5

mon

ths

22Andersen

et a

l. (1

997)

Amitriptyline(10‐200mg)

Cyproheptadine(2‐4mg)

Prophylactic

Pediatric

Retr

ospe

ctiv

e ch

art r

evie

wUSA

27Patientsfulfillingreferenced“diagnostic

criteriaforCVS”andtreated

prop

hyla

ctic

ally

.

50%

with

par

ent/

sibl

ing

with

mig

rain

e.

8/27

chi

ldre

n w

ith c

onco

mita

nt m

edic

al/

psychiatricconditions,including

depression,hyperactivity,and

deve

lopm

enta

l del

ay.

5 m

onth

s to

10

yea

rs

(b)

Aut

hor/

year

Out

com

es m

easu

red

Resu

ltsA

dver

se e

vent

s

1Badihianetal.(2018)

Primaryoutcomesmeasuredinlast2monthsofstudy:

a)Severityofattacks

b) M

edic

atio

n re

spon

se:

Completeremission:Completeresolutionofdisease

50‐9

9% re

miss

ion:

>50%decreasein#ordurationofattacks<50%

rem

issi

on:

<50%decreasein#ordurationofattacks

Completeremission:(

P‐va

lue

= 0.

206)

Amitriptyline:21/32(65.6%)

Cyproheptadine:16/32(50%)

50‐9

9% re

mis

sion

: (P

valu

e =

1)

Amitriptyline:8/32(25%)

Cyproheptadine8/32(25%)

<50%Remission:(

P va

lue

= 0.

1)

Amitriptyline3/32,9.4%

Cyproheptadine8/32,25%

Amitriptyline:3/32(9%)withsedativeeffects,

wei

ght g

ain

or c

onst

ipat

ion.

Non

e di

scon

tin‐

ued

med

icat

ion

Cyproheptadine:2/32(6%)withincreased

appe

tite

or te

mpo

rary

rest

less

ness

. Non

e di

scon

tinue

d m

edic

atio

n

1Sh

eare

r et a

l. (2

016)

Fullremission:Nofurtherattacksduring

follow‐upSubstantialimprovementin

symptoms:physician’sglobalassessment,with

areductioninthefrequencyofattacksofCVS

No

resp

onse

Fullremission:6/14(43%)

Subs

tant

ial i

mpr

ovem

ent:

2/14

(14%

) N

o re

spon

se: 3

/14

(21%

) Losttofollow‐up:3/14(21%)

Not

repo

rted

TAB

LE 2

(Continued)

(Continues)


(b)

Aut

hor/

year

Out

com

es m

easu

red

Resu

ltsA

dver

se e

vent

s

3Hikitaetal.(2016)

“Response”:lessthantwoattacksperyear

“Non‐responders”:morethanthreeattacksper

year

Resp

onde

r/N

on‐r

espo

nder

/Tot

al p

atie

nts

on li

sted

med

icat

ion

Valproicacid(9/4/15)

Valproicacidwithphenobarbital(4/0/4)

Phenobarbital(3/6/9)

Amitriptyline(1/4/5)Phenytoin(0/4/4)

Carbamazepine(0/2/2)Cyproheptadine(0/2/2)

Primidone(0/1/1)Propranolol(0/1/1)

Clonidinehydrochloride(0/1/1)

Not

repo

rted

4Sezeretal.(2016)

Responders:≥50%reductioninattacks

Non‐responders:<50%reductioninattacks

Noattacksfor1year(

P =

0.05

) Propranololgroup(13/22,59%)

Topiramategroup(13/16,81%)

≥50%decreaseinattacks/year(

P =

0.11

) Propranololgroup(5/22,23%)

Topiramategroup(2/16,13%)

Resp

onde

r rat

es (P=0.001)(Combinationofzeroattacks

and≥50%decrease)

(Acompositeendpoint):Propranolol18/22(81%)

Topi

ram

ate

grou

p 15

/16

(94%

) N

on‐r

espo

nder

rate

s (P

= 0

.01)

Propranolol4/22(18%)Topiramate1/16(6%)

Nodropoutsfromadverseevents.Nostatsig

differenceinadverseevents.

Topi

ram

ate

grou

p:

2patientswithdrowsinessanddizziness

Propranololgroup:

3patientswithdrowsiness,nervousness,and

dizziness.

5Jensenetal.(2015)

Them

atic

sat

urat

ion

Twothemesemergedfromthedata:

1)Perceivedlackofknowledgeamonghealthcareproviders

(difficultyreceivingadiagnosis,inappropriatetreatmentin

theacutecarefacility,avoidanceofcare)

2)ResponsetoCVS‐relatedtreatments(abortivetreatment,

self‐management)

a)Prophylactictreatment

‐4/16(25%)currentlyonTCAs.‐1/16(6%)statedthat“

Phenergan,ondansetron,amitriptyline,L‐carnitine,and

Co‐Q10haveallbeen“minimalintheirsuccesswithmy

treatments.”

b)Abortivetreatment

‐10/16(63%)saidondansetronwasmosteffectiveabortive

med

icat

ion

‐7/16(44%)saidbenzodiazepineseffective‐6/16(38%)said

antimigrainemedicationsleasteffectiveabortivemedication

c)Self‐Management

‐M

ariju

ana

use:

6/16(38%)usingMJ(dailyuseasprophylacticorabortive)

2/16(13%)triedMJbuthadnosymptomrelief

‐Hot‐waterbathing(11/16)69%(usedforhelpfulinnausea

and

pain

)

5/8thatusedMJalsoreportedhot‐waterbathing.

6/

16 (3

8%) d

escr

ibed

hot

‐wat

er b

athi

ng a

nd d

id n

ot d

iscu

ss

mar

ijuan

a co

nsum

ptio

n

TCAs:

1/4

repo

rted

som

nole

nce

6/16(38%)nolongertakingTCAsbecause“side

effects,ineffectiveness,orminimaleffective‐

ness.”Onepatientreported“severeconstipa‐

tion,drymouth,mentalsideeffects”

TAB

LE 2

(Continued)

(Continues)


(b)

Aut

hor/

year

Out

com

es m

easu

red

Resu

ltsA

dver

se e

vent

s

6M

oses

et a

l. (2

014)

Responsetoacutemedicationswasdefinedas

anyofthefollowing:

(1) d

ecre

ased

sev

erity

or

durationofacuteepisodes,(2)complete

resolutionofacuteepisodes,or(3)avoidance

ofemergencydepartmentvisit.

Resp

onse

to p

roph

ylac

tic m

edic

atio

ns w

as

definedasanyofthefollowing:

(1) r

esol

utio

n ofabnormalitiessinceinitiatingtreatment,

(2)decreasedfrequencyordurationofacute

episodes(withinthelast6months),or

(3)decreasednumberofemergency

depa

rtm

ent v

isits

(with

in th

e la

st 1

yea

r)

Prophylaxis:

Amitriptyline:23/40(58%)with“clinicalbenefit”

Cyproheptadine:30/61(49%)with“clinicalbenefit”

Abortive:

Ondansetron:56/85(66%)reported“improvement”

Not

repo

rted

7Treepongkarunaetal.

(201

4)Sh

ort‐t

erm

out

com

es(3‐6monthsafter

trea

tmen

t ini

tiatio

n)

Goodresponse:Remission(noattacksafter

trea

tmen

t) ORmarkedimprovement

Noresponse:<50%decreaseinattack

frequency

Long‐termoutcomes(atleast2‐yearfollow‐up

Frequencyofvomiting:

1)Excellent:noepisodes

2)Good:1‐2episodes

3)Poor:3ormoreepisodes/year

Shor

t‐ter

m o

utco

mes

Goodresponse:

Amitriptyline11/15(73%)(significantlybetterthanproprano

‐lo

l P =

0.0

4)

Propranolol5/14(36%)


Sodi

um v

alpr

oate

1/3

(33%

)

Long‐termoutcomes(diagnosis≥2years)

Dat

a av

aila

ble

on 1

9 pa

tient

s Amitriptyline:7/9(78%)patientswhohaditasafirst‐linedrug

hadgoodorexcellentresponse.

Propranolol:4/7(57%)hadgoodresponsewhenusedas

first‐linemedication

“Adversereaction”reportedin1patient,but

medicationinvolvedwasnotspecified

TAB

LE 2

(Continued)

(Continues)


(b)

Aut

hor/

year

Out

com

es m

easu

red

Resu

ltsA

dver

se e

vent

s

8Cristoforietal.(2014)

Primaryoutcome:(CVSepisodes)

Completeresponse:Noepisodes

Partialresponse:≥50%decreaseinboth

frequency(#episodes/year)andintensity

(epi

sode

dur

atio

n in

day

s)Noresponse:<50%decreaseinepisode

frequencyandintensity.

Seco

ndar

y ou

tcom

es:

NumberofCVSepisodes/yearNumberof

hosp

ital a

dmiss

ions

/yea

r CVSepisodeduration

Numberofvomits/hour

Symptom‐freeintervallength(days)

Scho

ol a

tten

danc

e pe

rcen

tage

Prophylacticgrouphadhigheraprepitantdosesthanthe

abor

tive

grou

p.

Alloutcomesbelowmeasuredat12months

Abortive:

1)Primaryoutcomes

Completeresponse:3/25(12%)

Partialresponse16/25(64%)Noresponse6/25(24%)

2)Secondaryoutcomes(Allstatisticallysignificant)

CVSepisodes/year:Baseline12(9.5‐16.5)to6(2‐8.5)

Hospitaladmissions/year:Baseline9(6‐12)to2.5(1‐5.5)

Durationofepisodes:Baseline5(3.5‐7)to1(0.75‐2)

Numbervomits/episode:Baseline9(7‐10)to4(2‐4.5)

Durationofinterepisodicperiod(days):Baseline30(21‐35)to

60 (4

0‐18

0)

%schoolattendance:Baseline65(57.5‐74)to80(72‐87.5)

Prophylaxis:

1)Primaryoutcomes

Completeresponse3/16(19%)

Partialresponse10/16(62%)

No

resp

onse

2/1

6 (1

9%)

2)Secondaryoutcomes(Allstatisticallysignificant)

CVSepisodes/year:Baseline12(9‐14)to3(2‐6)

Hospitaladmissions/year:Baseline8(6‐12)to2(1‐4)

Durationofepisodes:Baseline5(4‐7)to3(1‐3)

Numbervomits/episode:Baseline9(7‐10)to6(5‐8)

Durationofinterspersedperiod(days):Baseline30(21‐40)to

120

(60‐

180)

%Schoolattendance:Baseline67(58‐72)to81(78‐85)

Sideeffectsonlyinprophylacticgroup

affecting5/16(31%)

Hiccup3/16(19%)Asthenia/fatigue2/16

(12.

5%)

Incr

ease

d ap

petit

e 2/

16 (1

2.5%

) M

ild h

eada

che

1/16

(6%

) Se

vere

mig

rain

e 1/

16 (6

%)

Onl

y ch

ild w

ith m

igra

ine

stop

ped

med

icat

ion.

9Ku

mar

et a

l. (2

012)

Completeresponse(≥80%ameliorationin

symptomduration,frequency,andseverity)

Partialresponse(50‐80%reductioninsymptom

duration,frequency,andseverity)

Noresponse(<50%reductioninsymptom

duration,frequency,andseverity)

Completeresponsein44/76(58%).Ofthese,36/44~90%

takingTCAs,6/44~15%takingtopiramate,13/44~30%

takingL‐carnitine,13/44~30%takingCo‐Q10.

Partialresponseachievedin21/76(28%).Ofthese,20/21

~95%takingTCAs,8/21~40%takingtopiramate,11/21

~50%takingL‐carnitine,7/2135%takingCoQ‐10.

Noresponsein11/76(14%).Ofthese,8/11~70%takingTCAs,

3/1130%takingtopiramate,3/11~25%takingL‐carnitine,

and1/11~10%takingCoQ‐10.

Medication‐specificresponsedatathatwereprovided

Triptans:64/76(83%)couldabortepisodesHotshowers:

38/7

3 (5

2%) i

mpr

oved

(rep

orte

d in

25/

35 (7

1%) m

ariju

ana

user

s vs

19/

56 (3

4%) n

on‐u

sers

) (P=0.01).Coldshowers:

1/73

(1%

) im

prov

ed

Tric

yclic

ant

idep

ress

ants

: 18/70patients(26%)hadtostop(baddreams,

behavioralchanges,andincreased

som

nole

nce)

.

TAB

LE 2

(Continued)

(Continues)


(b)

Aut

hor/

year

Out

com

es m

easu

red

Resu

ltsA

dver

se e

vent

s

10Leeetal.(2012)

Responsetotreatment(“eitherdecreased

frequency/duration/intensityofattacks”)

ResponseofpediatricCVSpatientstomedication

TCA168/244(68%)

Propranolol79/91(87%)

L‐carnitineandamitriptyline23/30(77%)

Erythromycin13/20(65%)CoenzymeQ12/18(67%)

Phenobarbital11/14(78.6%)Valproate13/13(100%)

Pizotifen4/8(50%)


L‐Carnitine6/6(100%)

ResponseofadultCVSpatientstomedication

TCA180/237(76%)

Sum

atrip

tan

21/3

7 (5

7%)

Zonisamide/Levetiracetam15/20(75%)

Co‐Q105/7(71%)

Nostatisticallysignificantdifferencebetweenchildrenand

adul

ts

Not

repo

rted

11Bolesetal.(2011)

•Resolution(episodesresolved,allowingfor

one

epi

sode

a y

ear w

ith a

n ob

viou

s tr

igge

r).

•>75%improvement(between75and100%

resp

onse

in a

t lea

st o

ne e

piso

de p

aram

eter

*).

•>50‐75%improvement(between50and75%

resp

onse

in a

t lea

st o

ne e

piso

de p

aram

eter

*)

•Treatmentfailure(<50%improvementinboth

epis

ode

para

met

ers*

) *Episodeparameter=episodefrequencyand

epis

ode

dura

tion

Co‐Q10/L‐carnitine:

Reso

lutio

n: 3

pat

ient

s >75%improvement:3patients

Amitriptyline

Reso

lutio

n: 1

pat

ient

Treatmentfailure:1patient

Amitriptyline+Co‐Q10:

Resolution:3patients(inoneofthesecases,amitriptyline

wasnottolerated,yetepisodesresolvedontopiramate+

co‐enzymeQ10)

Amitriptyline+L‐carnitine:

Reso

lutio

n: 2

pat

ient

s

Amitriptyline+Co‐Q10+L‐carnitine:

Reso

lutio

n: 1

0 pa

tient

s >50%improvement:1patient

Treatmentfailure:2patientsCyproheptadine

Reso

lutio

n: 1

pat

ient

Cyproheptadine+Co‐Q10:

Reso

lutio

n: 1

pat

ient

Cyproheptadine+L‐Carnitine:

Reso

lutio

n 1

patie

nt

Cyproheptadine+Co‐Q10+L‐carnitine:Resolution:1patient

Topiramate±Co‐Q10orL‐carnitine

Re

solu

tion:

2 p

atie

nts

Amitriptyline:

2treatmentdiscontinuations(prolongedQTc,

narc

olep

sy)

1treatmentreduction(“behavioraland

emotionaleffects”)3non‐treatmentlimiting

sideeffect(increasedfrustrationintwo,one

alsowithinsomnia,onewithdizziness)

Co‐enzymeQ10:

1discontinuedbecauseofapseudo‐porphyria

rash

.

Cyproheptadine:

1 w

ith le

thar

gy

2with“vaguenon‐specificsensations”

TAB

LE 2

(Continued)

(Continues)


(b)

Aut

hor/

year

Out

com

es m

easu

red

Resu

ltsA

dver

se e

vent

s

12Hikitaetal.(2011)

Completeresponse:(novomitingafter

trea

tmen

t)

Effectiveresponse:(vomitingfrequency

reducedby>/=50%)

Non‐effectiveresponse:(thetreatmentwasnot

effectiveinpreventingvomiting)

11 p

atie

nts

rece

ived

sum

atrip

tan

subc

utan

eous

inje

ctio

n:

Completeresolution:4/11(36%)

Effectiveresponse:5/11(46%)

Non‐effectiveresponse:2/11(18%)

Patientswithafamilyhistorymigrainemorelikelytorespond

(definedascompleteandeffectiveresponse)(

P =

0.04

) 5

patie

nts

rece

ived

nas

al s

pray

: Completeresolution:1/5Effectiveresponse:1/5

Non‐effectiveresponse:3/5

Not

obs

erve

d

13Bolesetal.(2010)

Episodefrequency

Episodeduration

Numberofemeses

Nau

sea

seve

rity

Episodeimprovement:“compoundmeasure

‐mentscoredpositiveifatleastoneofthe

abovefourparameterswasscoredaspositive.”

Areductionofatleast50%ineachparameter

was

co‐

scor

ed a

s po

sitiv

e an

d an

y le

sser

re

spon

se a

s ne

gativ

e.

Amitriptyline*

Episodefrequency:88/162(54%)

Episodeduration:78/155(50%)

NumberofEmesis:70/154(45%)Nauseaseverity:68/157

(43%

) Episodeimprovement:127/177(72%)

CoenzymeQ10*

Episodefrequency:11/22(50%)

Episodeduration:8/22(36%)

Numberofemesis:8/20(40%)

Nau

sea

seve

rity:

11/

25 (4

4%)

Episodeimprovement:17/25(68%)

*Allreportedas50%reductioninasymptomStatistically

significantlyhigherpatientsatisfactionwithCoQ10

Amitriptylinesideeffects(statisticallyhigher

thanwithCoQ‐10)

Sideeffectsreported:102/202(50%)

Discontinuedduetosideeffects:42/198

(21%

) CoenzymeQ10:

Sideeffects:0/28(0%)

Discontinuedduetosideeffects:0/28(0%)

14Hejazietal.(2010)

FrequencyofCVSepisodesperyear

DurationofCVSepisodes(#days)

NumberofEDvisitsand/orhospitalizations

Outcomesmeasuredafterfirstandsecondyear

offollow‐upvisits.

FrequencyofCVSepisodes/year(Statisticallysignificantchangeat

Year

1 a

nd Y

ear 2

) Baseline17.8±8.3(4.5‐180)

Year15.4±3.8(1‐54)

Year23.3±2.8(1‐42)

DurationofCVSepisode(days):(StatsignificantchangeatYear1

and

Year

2)

Baseline6.7±6.1(0.2‐30)

Year12.5±2.7(0‐14)

Year22.2±2.4(0‐10)

#EDvisits/hospitalizations/year(StatsignificantchangeatYear1

and

Year

2)

Baseline15±13.4(1‐27)

Year14.2±5(0‐20)

Year23.3±3.6(0‐14)

36/4(88%)patients88%reportedlessEDvisits,decreased

frequency,anddurationofCVSepisodesandimprovedclinical

statusbasedonsubjectiveglobalassessment.Overahalfof

thosewhoagreedtostopMJduringfollow‐upindicateda

positiveimpactindecreasingCVSepisodes.

Sideeffectsin14/41(34%)(1/3ofthisgroup

need

ed to

redu

ce d

osag

e to

alle

viat

e si

de

effects)

Dry

mou

th 5

(12%

) Somnolence4(9%)Chronicfatigue3(7%)

Constipation2(4%)Blurredvision1(2%)

Mild

hal

luci

natio

ns 1

(2%

) 1

patie

nt s

topp

ed m

edic

atio

n du

e to

sev

ere

hallu

cina

tions

TAB

LE 2

(Continued)

(Continues)


(b)

Aut

hor/

year

Out

com

es m

easu

red

Resu

ltsA

dver

se e

vent

s

15Haghihatetal.(2007)

SeverityofCVSattacks

Frequencyofattacks

Amitriptyline(doesnotseemtobestatisticallysignificant)

Goodresponse(decreaseinthefrequencyandseverityof

attacks):46/83(56%)

Propranolol(statisticallysignificantly)

Goodresponse(decreaseinthefrequencyandseverityof

attacks):74/81(92%)

Amitriptyline:

“Significant”numberofhadsideeffectsof

includingirritability,agitation,insomnia,or

lethargy*(numberofpatientsnotspecified)

Propranolol:

Nosideeffectsreported

16N

amin

et a

l. (2

007)

CompletedCVSquestionnaire

HamiltonRatingScaleforAnxiety(HAM‐A),

Zung

Dep

ress

ion

Inve

ntor

y

VisualAnalogScale(Pain)at3months

VisualAnalogScale(Pain)after12months

Subj

ectiv

e im

prov

emen

t (SI

) in

daily

nau

sea

(After12months)

SI in

pai

n

SI in

vom

iting

Amitriptyline:

5patientshadimprovementinVASat3months:22/27(81%)

24patientsonamitriptylineforatleast3months:93%hada

“favorableresponsewithdecreasedfrequencyandseverityoftheir

symptoms.”

15/27tookatleast12monthsofamitriptyline:VASof6.1points

(significantmeanimprovementinsymptoms)

Show

ers:

72%

repo

rted

hot s

how

ers;

heat

ing

pads

and

lyin

g do

wn

in a

qui

et

setti

ng co

uld

amel

iora

te o

r com

plet

ely

relie

ve th

eir s

ympt

oms.

Marijuana(MJ)use:

13/31dailyuse(7/13thoughtMJtherapeutic,2/13saidCVS

resolvedafterstoppingMJ,4/13saidnorelationshipbetweenMJ

and

sym

ptom

s).

Amitriptyline:1/27discontinued:

hype

rsom

nia

and

palp

itatio

ns.

17Clouseetal.(2007)

Reductionofvomitingepisodes

FrequencyofvomitingEpisodes

Likertscale:(Score>/=2forfavorableclinical

resp

onse

)

0:nosignificantimprovementorworse

1:slightimprovement,requiringtreatment

chan

ges

2:moderateimprovement,regimenstablebut

sym

ptom

s no

t com

plet

ely

reso

lved

3:

clin

ical

rem

issi

on a

nd c

ompl

ete

patie

nt

satisfaction

Interviewdataobtainedat“pointoflast

clinicalcontact”

Chartreview:

Favorableoutcome—15/20(75%)

Zonisamide:12/16andLevetiracetam:3/4(nostatistical

difference)

Inte

rvie

win

g:

Impr

oved

ove

rall

(18/

20) (

2/16

no

chan

ge)

Lessseverevomiting(12/16)(4/16nochange)

Shor

ter e

piso

des

(7/1

6) (9

/16

no c

hang

e)

Frequencyofvomitingepisodesdecreasedsignificantlyafter

initiationofantiepilepticdrugtherapy(1.3to0.5episodes/

mon

th)

Medicationsideeffectsclassifiedas:Severe:

fatigue,confusion,headache,anddizziness

Moderate:depression,muscleweakness,

dizziness,difficultysleeping,poorconcentration/

memory,confusion,ortiredness/fatigue

Mild:agitation/irritability,poorappetite,runny

nose/cough,difficultysleeping,poorconcentra

‐tion/memory,headache,confusion,andtiredness/

fatigue

Severesideeffects:reportedin4patients,which

wereeliminatedin75%(3/4)ofsubjectsonce

switc

hed

to th

e ot

her a

ntie

pile

ptic

(inclu

ding

1

patie

nt w

ith a

ngio

edem

a on

leve

tirac

etam

). 1/

20

repo

rted

antie

pile

ptic

drug

s int

oler

able

des

pite

sw

itchi

ng d

rugs

or d

osag

e.

Moderatesideeffects:5/20

Mildsideeffects:4/20

TAB

LE 2

(Continued)

(Continues)


(b)

Aut

hor/

year

Out

com

es m

easu

red

Resu

ltsA

dver

se e

vent

s

18Bolesetal.(2006)

“Treatmentbenefit”(specificsnotdefined)

Treatment(includesCVS+andCVS‐groups)

Prophylactic(reportedbenefit)*

Amitriptyline16/31(52%)


Propranolol:5/15(33%)

Abortive(reportedbenefit)*

IVDextrose:21/24(88%)

O

ndan

setr

on 4

2/52

(81%

)

Lorazepam:23/30(77%)

Promethazine:13/23(57%)

Su

mat

ripta

n: 8

/8 (1

00%

)

Prophylactic

Amitriptyline:5/31withlethargy(2subjects),

moodswings,abdominalcramping,and

sync

ope

Cyproheptadine:3/18withweightgain(2),

behavioralchange,andhallucinations

Propranolol:0/15

Abortive

IVDextrose:0/21

O

ndan

setr

on: 2

/42

with

pal

pita

tions

and

al

lerg

y

Lorazepam:2/30with“untoward”reaction*

Promethazine:0/23Sumatriptansuccinate:

1/8

with

hal

luci

natio

ns19

Aanpreungetal.

(200

2)Goodresponse:absenceofvomitingorfew

episodesofvomiting

Fairresponse:persistenceofvomitingbut

improvementwithlessfrequencyandless

intenseepisodesofvomiting

Poorresponse:noresponse.

SeverityofdiseaseSevere(>20emeses/day)

Mod

erat

e (1

0‐19

em

eses

/day

) Mild(<10emeses/day)

Medication“effective”ifgood/fairresponse.

Medication“non‐effective”ifpoorresponse.

Pizotifen:8/25receivedpizotifen

Goodresponse:3(2withmilddisease,1withmoderate)

Fairresponse:1(1withseveredisease)

Poorresponse:4(3hadseveredisease)In3patients,pizotifen

chan

ged

to a

mitr

ipty

line

Amitriptyline

(18/

25 p

aten

ts re

ceiv

ed)

Goodresponse:11(4withmilddisease,5withmoderate,2

with

sev

ere)

Fairresponse:4(2withmilddisease,2withmoderate

dise

ase)

N

o re

spon

se: 3

(3 w

ith s

ever

e di

seas

e)

Propranolol (

2/25

rece

ived

) Goodresponse:1(1withmoderatedisease)

No

resp

onse

: 1 (1

with

sev

ere

dise

ase)

Nostatisticaldifferenceinresponsebetweenpizotifenand

amitr

ipty

line

No

adve

rse

even

ts o

bser

ved

20Prakashetal.(1999)

Completeremissionofsymptoms(ratingof3)

Partialresponse(ratingof2)

Likert‐typeresponsescale:

0:nosignificantimprovementorworse;1:

slig

ht im

prov

emen

t

2: m

oder

ate

impr

ovem

ent

3: c

linic

al re

mis

sion

CVSgroup:Completeremission:3/17(17.6%)

Partialresponse:10/17(58.8%)

Noresponse:4/17(23.5%)Responsewasmanifestas

decreasedcyclefrequency(3,17.6%),decreasedintensityof

symptoms(6,35.3%),andshorteningofthevomitingcycles

(1,5.9%).

4/17(23.5%)hadsideeffectsthatincluded

sedation,emotionallability,andsleep

dist

urba

nces

. No

disc

ontin

uatio

n du

e to

sid

e effects.

TAB

LE 2

(Continued)

(Continues)


(b)

Aut

hor/

year

Out

com

es m

easu

red

Resu

ltsA

dver

se e

vent

s

21Lietal.(1999)

Dem

ogra

phic

cha

ract

eris

tics

VomitingpatternAssociatedsymptoms

TriggeringeventsMedicationresponse(>50%

redu

ctio

n in

vom

iting

or e

piso

des)

Nostatisticallysignificantdifferencebetweenmigraine‐associated

andnon–migraine‐associatedCVS

Med

icatio

n re

spon

se (a

borti

ve a

nd p

roph

ylac

tic)

Propranolol(migraine‐associatedCVS(52/73(71%)vsnon‐mi‐

graineCVS(8/2138%)

Cyproheptadine(migraine‐associatedCVS(15/32(47%))vs

non‐migraineCVS(0/5pts)

Amitriptyline(migraine‐associatedCVS(12/16(75%)vsnon‐mi‐

graineCVS(1/1(100%))Sumatriptan(migraine‐associatedCVS

(24/35(69%))vsnon‐migraineCVS(1/3(33%).Nostatistically

significantdifferenceinsumatriptanusagebetweengroups

Non

e re

port

ed

22Andersenetal.(1997)

Completeresponse:noattacks

Partialresponse:≥50%reductioninfrequency

ofattacks

Noresponse:<50%decreaseinfrequencyof

attacks

Completeremission

Amitriptyline16/22(73%)


Partialremission



No

resp

onse


Cyproheptadine:1/6(16.7%)

“Sideeffectsforbothmedicationsincluded

seda

tion

and

wei

ght g

ain

due

to in

crea

sed

appetite.”Specificnumbersnotprovided.

TAB

LE 2

(Continued)

2.4.2 | Study selection criteria

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.

http://covidence.org

http://www.cebm.brown.edu/openmeta/


2.7 | Evidence‐to‐decision framework

Informationfromthisreviewwasusedincombinationwithfactorssuchaspatients’valuesandpreferences,cost‐effectivenessdata(ifavailable),andresourceutilizationtoinformthedevelopmentoftheclinical guideline.

3 | RESULTS

3.1 | Overview

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?

Key messageThereisverylowcertaintyintheevidencethatTCAsshouldbeusedasprophylactictherapyinCVS.SeeTable3forfullevidenceprofile.

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%).


TAB

LE 3

ShouldTCAsbeusedasprophylactictherapyinadultswithCVS?

Cert

aint

y as

sess

men

t№

of p

atie

nts

Effe

ct

Cert

aint

yIm

port

ance

№ o

f stu

dies

Stud

y de

sign

Risk

of b

ias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

TCA

sPl

aceb

oRe

lativ

e (9

5% C

I)A

bsol

ute

(95%

CI)

Complete/Partialresponseorsymptomimprovement(variablydefinedineachstudy;follow‐uprange5monthsto5years)

14O

bser

vatio

nal

stud

ies

a Se

rious

b Se

rious

c Se

rious

d N

ot s

erio

us

Non

e 413/600(70%;range61‐77%)ofpatients

had

com

plet

e or

par

tial r

espo

nse

to

trea

tmen

t or s

ympt

om im

prov

emen

t ac

ross

14

stud

ies

⨁◯

◯◯VERY

LOW

CRITICAL

ReductionindurationorseverityofCVSsymptoms;follow‐up2years

1Hejazi2010

Obs

erva

tiona

l study,n=41

Not

ser

ious

N

ot s

erio

usN

ot s

erio

usSe

rious

e N

one

ReductionindurationofCVSepisodes

frombaseline6.7±6.1(days)to2.2±2.4

(day

s).

⨁◯

◯◯VERY

LOW

IMPORTANT

Reductioninnumberofepisodes;follow‐up2years

1Hejazi2010

Obs

erva

tiona

l study,n=41

Not

ser

ious

Not

ser

ious

Not

ser

ious

Serio

use

Non

e Reductioninnumberofepisodesfrom

baseline(mean)17.8±8.3to3.3±2.8.

⨁◯

◯◯VERY

LOW

IMPORTANT

Reductioninhospitalizations/EDvisits

1Hejazi2010

Obs

erva

tiona

l study,n=41

Not

ser

ious

Not

ser

ious

Not

ser

ious

Serio

use

Non

e Reductioninnumberofhospitalizations

reported:baseline15±13.4downto

3.3±3.6.

⨁◯

◯◯VERY

LOW

IMPORTANT

Adverseeffectsleadingtotreatmentdiscontinuationf

See

narr

ativ

e.⨁

◯◯

◯VERY

LOW

IMPORTANT

a Overall,14studies(includingtheinterventionarmfrom2RCTs)wereincludedinthisanalysis.

b Therewereissuesaroundselectionbias,nointentiontotreatanalysis,confounding,co‐interventionswithmitochondrialsupplements,andvariablefollow‐up.Theoutcomeswerevariablyreported

acrossthedifferentstudies:fromcompleteresponse(noattacks),partialresponse(50%reductioninfrequencyandduration)to“goodresponse,fairresponse,poorresponse,”totheuseofavisual

analogscaleto“subjectiveimprovement.”

c Werateddownforinconsistency(highI‐squared).

d Werateddownforindirectnessas6studieswereconductedinthepediatricpopulation.

e Therewerefewevents,andthesamplesizewassmall.

f Variablyreportedacrossstudies.Seenarrative.


TAB

LE 4

ShouldtopiramatebeusedasprophylactictherapyinadultswithCVS?

Qua

lity

asse

ssm

ent

№ o

f pat

ient

sEf

fect

Qua

lity

Impo

rtan

ce№

of s

tudi

esSt

udy

desi

gnRi

sk o

f bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

nsVa

lpro

ic a

cid

Rela

tive

(95%

CI)

Abs

olut

e (9

5% C

I)

Completeresponse(freefromattackforatleast1year)

1Sezer2016

Obs

erva

tiona

l study,N=16

Not

ser

ious

a N

ot s

erio

us

Serio

usb

Serio

usc

Non

e 81%werefreefromattacksat12months

⨁◯

◯◯

VERYLOW

CRITICAL

Partialresponse(50%reductioninbothfrequencyandintensityofCVSsymptoms);follow‐up12months

1O

bser

vatio

nal

study,N=16

Not

ser

ious

a N

ot s

erio

us

Serio

usb

Serio

usc

Non

e 13

% a

chie

ved

a pa

rtia

l res

pons

e (5

0%

redu

ctio

n in

sym

ptom

s)⨁

◯◯

◯

VERYLOW

CRITICAL

ReductionindurationorseverityofCVSsymptoms;follow‐up12months

1O

bser

vatio

nal

study,N=16

Not

ser

ious

a N

ot s

erio

us

Serio

usb

Serio

usc

Non

e Reductioninmediandurationofcycles

frombaseline17.0±5.1to

11.0±2.2hours.Reductioninepisodesof

vomitingpercyclefrombaseline14.0±2.3

to12.0±1.4

⨁◯

◯◯

VERYLOW

IMPORTANT

Reductioninnumberofepisodes;follow‐up12months

1O

bser

vatio

nal

study,N=16

Not

ser

ious

a N

ot s

erio

us

Serio

usb

Serio

usc

Non

e Decreaseinnumberofattacksperyear

from5.0±0.1to1.0±0.4

⨁◯

◯◯

VERYLOW

IMPORTANT

Reductioninhospitalizations/EDvisits—NOTREPORTED

Adverseeffectsleadingtotreatmentdiscontinuation;follow‐up12months

1O

bser

vatio

nal

study,N=13

Not

ser

ious

a N

ot s

erio

us

Serio

usb

Serio

usc

Non

e N

one

obse

rved

⨁◯

◯◯

VERYLOW

IMPORTANT

a This

was

a re

tros

pect

ive

stud

y ba

sed

on c

hart

revi

ew.

b Thestudy(Sezer2016)included16pediatricpatients.Overallresponders(≥50%reduction)=94%(partialorcompleteresponse).Inoneadditionalstudy(Kumar2012),17/76adultpatientsreceived

topiramatebuttherewasnotenoughdetailprovidedfortheanalysis(aspatientsmayalsohavebeentreatedwithamitriptylineandmitochondrialsupplements.Inthisstudy,overallresponsewas86%(≥

50%reductioninfrequencyofCVSepisodes).

c Therewerefeweventsandsmallnumbersofpatients.


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?

Key messageInpatientswithCVS,thereisverylowcertaintyintheevidencefortheuseofaprepitantasprophylactictherapyinCVS.SeeTable5forfullevidenceprofile

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?

Key messageInpatientswithCVS,thereisverylowcertaintyintheevidencefortheuseofzonisamideorlevetiracetamasprophylactictherapy.SeeTable6forfullevidenceprofile

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).


TAB

LE 5

ShouldaprepitantbeusedasprophylactictherapyinadultswithCVS?

Cert

aint

y as

sess

men

t

Impa

ct

Cert

aint

yIm

port

ance

№ o

f stu

dies

Stud

y de

sign

Risk

of b

ias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

Completeresponse(noepisodes)(follow‐up:12months)

1Cristofori

2014

Obs

erva

tiona

l study,n=16

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

e3/16(19%)ofpatientshadno

furtherepisodesat12months

⨁◯

◯◯VERY

LOW

CRITICAL

Partialresponse:≥50%decreaseinbothfrequency(#episodes/year)andintensity(episodedurationindays);follow‐up:12months

1 O

bser

vatio

nal

study,n=16

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

e10

/16

(62%

) had

a p

artia

l re

spon

se⨁

◯◯

◯VERY

LOW

IMPORTANT

CVSepisodeduration(follow‐up:12months)

1 O

bser

vatio

nal

study,n=16

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

eReductioninthedurationof

episodes(days):Baseline5

(4‐7

) to

3 (1

‐3).

Redu

ctio

n in

nu

mbe

r vom

its/e

piso

de:

Baseline9(7‐10)to6(5‐8).

⨁◯

◯◯VERY

LOW

IMPORTANT

ReductioninnumberofCVSepisodes/year(follow‐up:12months)

1 O

bser

vatio

nal

study,n=16

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

eCVSepisodes/year:Baseline12

(9‐1

4) to

3 (2

‐6) a

t 12

mon

ths

⨁◯

◯◯VERY

LOW

IMPORTANT

Reductioninhospitalizations/year(follow‐up:12months)

1 O

bser

vatio

nal

study,n=16

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

eReductioninnumberofhospital

admissions/yearfrombaseline

8 (6

‐12)

to 2

(1‐4

) at 1

2 m

onth

s

⨁◯

◯◯VERY

LOW

IMPORTANT

Symptom‐freeintervallength(days)(follow‐up:12months)

1 O

bser

vatio

nal

study,n=16

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

eDurationofinterspersedperiod

(days):Baseline30(21‐40)to

120

(60‐

180)

at 1

2 m

onth

s

⨁◯

◯◯VERY

LOW

IMPORTANT

Schoolattendance(follow‐up:12months)

1 O

bser

vatio

nal

study,n=16

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

eIn

crea

se in

sch

ool a

tten

danc

e:

67%

(58‐

72) t

o 81

% (7

8‐85

) at

12 m

onth

s

⨁◯

◯◯VERY

LOW

IMPORTANT

Adverseeffects(follow‐up:12months)

c

1 O

bser

vatio

nal

study,n=16

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

eO

nly

one

child

with

mig

rain

e st

oppe

d th

e m

edic

atio

n (1

/16)

⨁◯

◯◯VERY

LOW

IMPORTANT

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

migraine(1/16,6%).


TAB

LE 6

Should(antiepileptics)zonisamideorlevetiracetambeusedasprophylactictherapyinadultswithCVS?

Cert

aint

y as

sess

men

t

Impa

ct

Cert

aint

yIm

port

ance

№ o

f stu

dies

Stud

y de

sign

Risk

of b

ias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

co

nsid

erat

ions

SymptomaticImprovementassessedbyLikertscale:0(nosignificantimprovement/worse)to3(clinicalremissionandcompletesatisfaction);follow‐up~9monthsa

1Clouse

(200

7)O

bser

vatio

nal

study,n=20

Serio

us a

Not

ser

ious

Se

rious

b Se

rious

c N

one

“Favorableoutcome”15/20(chart

review);“Better”18/20patients

(pat

ient

inte

rvie

ws)

; 12/

16 h

ad

less

sev

ere

vom

iting

(4: n

o ch

ange

); 7/

16 h

ad s

hort

er

epis

odes

(9: n

o ch

ange

)

⨁◯

◯◯VERY

LOW

CRITICAL

Reductioninnumberofepisodes/episodefrequency(permonth);medianfollow‐up~9months

1 O

bser

vatio

nal

study,n=20

Serio

us a

Not

ser

ious

Se

rious

b Se

rious

c N

one

Reductioninthenumberof

episodespermonth:Baseline:

1.3±0.3to0.5±0.2episodes/

mon

th

⨁◯

◯◯VERY

LOW

IMPORTANT


Adverseeffects(AEs);follow‐up~9monthse

1 O

bser

vatio

nal

study,n=20

Serio

us a

Not

ser

ious

Se

rious

b Se

rious

c N

one

SevereAEs:4/20(20%).One

subj

ect o

n le

vetir

acet

am

developedangioedema,which

reso

lved

whe

n sw

itche

d to

zonisamide.Onesubject

discontinuedtherapyinspiteof

switc

hing

dru

gs a

nd d

osag

es

⨁◯

◯◯VERY

LOW

IMPORTANT

a Ascore≥2wasrequiredfora“favorable”clinicalresponse.“Better”asaclinicalresponsewasnotdefined.Likertscale:0=nosignificantimprovementorworse;1=slightimprovement,requiring

treatmentchanges;2=moderateimprovement,regimenstablebutsymptomsnotcompletelyresolved;and3=clinicalremissionandcompletepatientsatisfactionwiththerapy.Ofthe20patientswitha

“favorable”clinicalresponse,12/16receivedzonisamideand3/4receivedlevetiracetam.

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

weakness,dizziness,difficultysleeping,poorconcentration/memory,confusion,ortiredness/fatigue(5/20).


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

BLE

7 ShouldmitochondrialsupplementsbeusedasprophylactictherapyinadultswithCVS?

Qua

lity

asse

ssm

ent

№ o

f pat

ient

sEf

fect

Qua

lity

Impo

rtan

ce№

of s

tudi

esSt

udy

desi

gnRi

sk o

f bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

nsM

itoch

ondr

ial

supp

lem

ents

*Re

lativ

e (9

5% C

I)A

bsol

ute

(95%

CI)

Complete/Partialresponse—NOTREPORTED

ReductionindurationorseverityofCVSsymptoms

1Boles(2010)

Obs

erva

tiona

l study,N=32

Not

ser

ious

a N

ot s

erio

us

Serio

usb

Serio

usc

Non

e UsingvaryingdosesofCoQ10,68%of

subj

ects

had

impr

ovem

ent i

n sy

mpt

oms.

⨁◯

◯◯

VERYLOW

IMPORTANT

Reductioninnumberofepisodes—NOTREPORTED

IMPORTANT

Adverseeffectsleadingtotreatmentdiscontinuation

1Boles(2010)

Obs

erva

tiona

l study,N=28

Not

ser

ious

a N

ot s

erio

us

Serio

usb

Serio

usc

Non

e Outof28participantsonCoQ10,0side

effectswerereported.

⨁◯

◯◯

VERYLOW

IMPORTANT

a This

was

a re

tros

pect

ive

stud

y ba

sed

on c

hart

revi

ew.

b The

stud

ies

incl

uded

adu

lt an

d pe

diat

ric p

atie

nts.

c Therewerefeweventsandsmallnumbersofpatients.


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?

NopublishedstudiesexaminingtheuseofondansetronasabortivetherapyforCVSwereidentifieddespiteitswidespreaduseinCVS.NoGRADEevidenceprofilewascreated.


TAB

LE 8

ShouldtriptansbeusedasabortivetherapyinadultswithCVS?

Qua

lity

asse

ssm

ent

№ o

f pa

tient

sEf

fect

Qua

lity

Impo

rtan

ce№

of s

tudi

esSt

udy

desi

gnRi

sk o

f bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

nstr

ipta

nsRe

lativ

e (9

5%

CI)

Abs

olut

e (9

5% C

I)

Treatmentresponse(variablydefinedineachstudy)

3 Ku

mar

(201

2)

Hikita(2011)Li

(199

9_

Obs

erva

tiona

l st

udie

s Se

rious

a ,b

Not

ser

ious

Se

rious

c Se

rious

d N

one

Therangeofeffectswas36‐82%

resp

onse

(acr

oss

the

3 st

udie

s) in

ab

ortin

g an

epi

sode

or p

reve

ntin

g an

attack

⨁◯

◯◯

VERYLOW

CRITICAL

INDIRECTEVIDENCE‐Reliefof(orimprovementin)nauseawithin2hoursinmigraineheadachepatientse

8Randomized

tria

ls (o

verv

iew

ofsrs)

Not

ser

ious

N

ot s

erio

us

Serio

use

Not

ser

ious

N

one

Therangeofeffectsforreductionin

naus

ea s

ympt

oms

with

in 2

hou

rs w

as

45%to76%(across8RCTs);higher

ratesofsymptomimprovementwere

seen

with

intr

anas

al (5

0‐60

% ra

nge)

an

d su

bcut

aneo

us m

edic

atio

n (7

6%).

⨁⨁

⨁◯

MODERATE

CRITICAL

ReductioninnumberofCVSepisodes

1Hikita(2011)

Obs

erva

tiona

l study,n=12

Serio

usa

Not

ser

ious

Serio

usf

Serio

usd

Non

e In11patientswith35attacks,response

wasseenin19attacks(subcutaneous).

In5patientswith6attacks,response

wasseenin2attacks(nasalspray).

⨁◯

◯◯

VERYLOW

IMPORTANT


Adverseeffectsleadingtotreatmentdiscontinuationg

3O

bser

vatio

nal

stud

ies

Serio

usa

Not

ser

ious

Serio

usc

Serio

usd

Non

eN

o ad

vers

e ev

ents

obs

erve

d ac

ross

the

threestudiesinCVSpatients.

⨁◯

◯◯

VERYLOW

IMPORTANT

a Theobservationalstudieswereatriskforselectionbias.

b Theoutcomewasvariablydefinedacrossstudies:“medicationresponse”or“benefit”whichmayrepresentcomplete/partialresponseorsymptomimprovement.Lietal.foundthat69%ofkids(24/35)

hadimprovementinnauseasymptoms(definedasa>50%reductioninvomitingepisodeswithsubcutaneoussumatriptan).Hikitaetal.found54%ofattacksin11kids/1adultwereresponsiveto

sumatriptantherapy(definedascompleteimprovementoratleasta50%reductioninvomitingfrequency).

c Somestudieswereconductedinpediatricpopulations,andsomedatacomefromaCVS–migraine‐associatedphenotype.

d Werateddownforimprecisionduetothesmallsamplesizeandfewevents.

e AnoverviewofSRswasusedtoprovideindirectevidencetosupporttheuseoftriptansfornauseaandvomiting.These8studieswereconductedinindividualswithmigraineheadaches,andnausea

reliefwasasecondaryoutcome.ThisestimatewasderivedfromtheCochraneoverviewofSRsby

Der

ry e

t al.

Sum

atrip

tan

(all

rout

es o

f adm

inist

ratio

n) fo

r acu

te m

igra

ine

atta

cks i

n ad

ults

‐ove

rvie

w o

f Co

chra

ne re

view

s. Co

chra

ne D

atab

ase

of S

yste

mat

ic R

evie

ws 2

014,

Issu

e5, A

rt. N

o. C

D00

9108

. f TheHikita2011studyincluded1adultand11pediatricpatients.

g NodataonadverseeventsleadingtotreatmentdiscontinuationwereprovidedintheDerryetal.SR.AEsweregenerallydescribedasmildormoderateandself‐limited.Nocardiovascularproblems

wer

e no

ted.


TAB

LE 9

ShouldaprepitantbeusedasabortivetherapyinadultswithCVS?

Cert

aint

y as

sess

men

t

Impa

ct

Cert

aint

yIm

port

ance

№ o

f st

udie

sSt

udy

desi

gnRi

sk o

f bia

sIn

cons

iste

ncy

Indi

rect

ness

Impr

ecis

ion

Oth

er

cons

ider

atio

ns

Completeresponse(noepisodes)(follow‐up:12months)

1Cristofori

(201

4)O

bser

vatio

nal

studies,n=25

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

e3/25(12%)ofpatientshadno

furtherepisodes

⨁◯

◯◯VERYLOW

CRITICAL

Partialresponse:(≥50%decreaseinbothfrequency(#episodes/year)andintensity(episodedurationindays))(follow‐up:12months)

1 O

bser

vatio

nal

studies,n=25

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

e16/25(64%)ofpatientshad

part

ial r

espo

nse

⨁◯

◯◯VERYLOW

CRITICAL

CVSepisodeduration(follow‐up:12months)

1 O

bser

vatio

nal

studies,n=25

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

eReductionindurationof

episodes:Baseline5(3.5‐7)to1

(0.7

5‐2)

. Red

uctio

n in

num

ber

vomits/episode:Baseline9

(7‐1

0) to

4 (2

‐4.5

).

⨁◯

◯◯VERYLOW

IMPORTANT

ReductioninnumberofCVSepisodes/year(follow‐up:12months)

1 O

bser

vatio

nal

studies,n=25

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

eCVSepisodes/year:Baseline12

(9.5

‐16.

5) to

6 (2

‐8.5

) at

12 m

onth

s

⨁◯

◯◯VERYLOW

IMPORTANT

Reductioninhospitalizations/year(follow‐up:12months)

1 O

bser

vatio

nal

studies,n=25

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

eReductioninnumberofhospital

admissions/year:Baseline9

(6‐1

2) to

2.5

(1‐5

.5)

⨁◯

◯◯VERYLOW

IMPORTANT

Symptom‐freeintervallength(days)(follow‐up:12months)

1 O

bser

vatio

nal

studies,n=25

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

eDurationofinterspersedperiod

(days):Baseline30(21‐35)to60

(40‐

180)

at 1

2 m

onth

s

⨁◯

◯◯VERYLOW

IMPORTANT

Schoolattendance(follow‐up:12months)

1 O

bser

vatio

nal

studies,n=25

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

e In

crea

se in

sch

ool a

tten

danc

e:

65%

(57.

5‐74

) to

80%

(72‐

87.5

) at

12

mon

ths

⨁◯

◯◯VERYLOW

IMPORTANT

AdverseEventsleadingtotreatmentdiscontinuation(follow‐up:12months)

1 O

bser

vatio

nal

studies,n=25

Serio

usa

Not

ser

ious

Se

rious

b N

ot s

erio

us

Non

e N

one

repo

rted

in a

bort

ive

grou

p⨁

◯◯

◯VERYLOW

IMPORTANT

a Thiswasaretrospectivecohortstudywithnocontrolpopulationandconcernsaboutpossibleselectionbias.Thestudyincludedcohortswhoreceivedprophylaxisandabortivetreatment.Onlythe

patie

nts

who

rece

ived

abo

rtiv

e th

erap

y ar

e pr

esen

ted

here

. b ThepatientpopulationincludedpediatricpatientsthatfailedpriorCVStreatmentsandwereonseveralconcomitantmedications.


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?

Nopublishedstudieswerefoundthatexplicitlyaddressedthisques‐tion.NoGRADEevidenceprofilewascreated.

3.3.5 | Should meditation, relaxation, and biofeedback be used as complementary therapy in adults with CVS?

Nopublishedstudieswerefoundthatexplicitlyaddressedthisques‐tion.NoGRADEevidenceprofilewascreated.

3.3.6 | Areas of limited/insufficient evidence

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.

ACKNOWLEDG MENTS

WearegratefultoDr.BensonMasseywhosecounselandguidancehavebeeninvaluableincompletingthiswork.

DISCLOSURE S

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.

https://doi.org/10.1111/nmo.13605

https://doi.org/10.1111/nmo.13605

management of cyclic vomiting syndrome in adults: evidence

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