management of cyclic vomiting syndrome in adults: evidence
TRANSCRIPT
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
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.
| 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
4 of 29 | SHARAF et Al.
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)
| 5 of 29SHARAF et Al.
(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)
6 of 29 | SHARAF et Al.
(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)
| 7 of 29SHARAF et Al.
(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)
8 of 29 | SHARAF et Al.
(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)
| 9 of 29SHARAF et Al.
(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)
10 of 29 | SHARAF et Al.
(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)
| 11 of 29SHARAF et Al.
(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%)
Cyproheptadine0/4(0%)
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)
12 of 29 | SHARAF et Al.
(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)
| 13 of 29SHARAF et Al.
(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%)
Cyproheptadine5/6(83%)
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)
14 of 29 | SHARAF et Al.
(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)
| 15 of 29SHARAF et Al.
(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)
16 of 29 | SHARAF et Al.
(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%)
Cyproheptadine11/18(61%)
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)
| 17 of 29SHARAF et Al.
(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%)
Cyproheptadine:4/6(66%)
Partialremission
Amitriptyline:4/22(18%)
Cyproheptadine:1/6(17%)
No
resp
onse
Amitriptyline:2/22(10%)
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.
18 of 29 | SHARAF et Al.
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%).
| 19 of 29SHARAF et Al.
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.
20 of 29 | SHARAF et Al.
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.
| 21 of 29SHARAF et Al.
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).
22 of 29 | SHARAF et Al.
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%).
| 23 of 29SHARAF et Al.
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
Reductioninhospitalizations/EDvisits—NOTREPORTED
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).
24 of 29 | SHARAF et Al.
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.
| 25 of 29SHARAF et Al.
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.
26 of 29 | SHARAF et Al.
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
Reductioninhospitalizations/EDvisits—NOTREPORTED
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.
| 27 of 29SHARAF et Al.
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.
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?
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.
R E FE R E N C E S
1. Abu‐Arafeh I, Russell G. Cyclical vomiting syndrome in chil‐dren: a population‐based study. J Pediatr Gastroenterol Nutr. 1995;21:454‐458.
| 29 of 29SHARAF et Al.
2. SagarRC,SoodR,GracieDJ,etal.Cyclicvomitingsyndrome isaprevalentandunder‐recognizedconditioninthegastroenterologyoutpatient clinic. Neurogastroenterol Motil.2018;30:????‐????.
3. GuyattGH,OxmanAD,VistGE,etal.GRADE:anemergingconsen‐susonratingqualityofevidenceandstrengthofrecommendations.BMJ. 2008;336:924‐926.
4. AanpreungP,VajaradulC.Cyclicvomiting syndrome inThai chil‐dren. J Med Assoc Thai. 2002;85(Suppl 2):S743‐S748.
5. AndersenJM,SugermanKS,LockhartJR,WeinbergWA.Effectiveprophylactic therapy for cyclic vomiting syndrome in childrenusing amitriptyline or cyproheptadine. Pediatrics. 1997;100: 977‐981.
6. Badihian N, Saneian H, Badihian S, Yaghini O. ProphylacticTherapyofCyclicVomitingSyndrome inChildren:ComparisonofAmitriptylineandCyproheptadine:ARandomizedClinicalTrial.Am J Gastroenterol. 2018;113:135‐140.
7. BolesRG,Lovett‐BarrMR,PrestonA,LiBU,AdamsK.Treatmentofcyclicvomitingsyndromewithco‐enzymeQ10andamitriptyline,aretrospective study. BMC Neurol. 2010;10:10.
8. BolesRG.Highdegreeofefficacyinthetreatmentofcyclicvomit‐ingsyndromewithcombinedco‐enzymeQ10,L‐carnitineandami‐triptyline,acaseseries.BMC Neurol. 2011;11:102.
9. HaghighatM,RafieSM,DehghaniSM,FallahiGH,NejabatM.Cyclicvomiting syndrome in children: experience with 181 cases fromsouthern Iran. World J Gastroenterol. 2007;13:1833‐1836.
10. Hejazi RA, Reddymasu SC, Namin F, Lavenbarg T, Foran P,McCallumRW.Efficacyoftricyclicantidepressanttherapyinadultswithcyclicvomitingsyndrome:a two‐year follow‐upstudy.J Clin Gastroenterol. 2010;44:18‐21.
11. Hikita T, Kodama H, Ogita K, Kaneko S, Nakamoto N, MimakiM. Cyclic Vomiting Syndrome in Infants and Children: A ClinicalFollow‐UpStudy.Pediatr Neurol. 2016;57:29‐33.
12. Kumar N, Bashar Q, Reddy N, et al. Cyclic Vomiting Syndrome(CVS):isthereadifferencebasedononsetofsymptoms–pediatricversusadult?BMC Gastroenterol. 2012;12:52.
13. Moses J, Keilman A, Worley S, Radhakrishnan K, Rothner AD,ParikhS.Approachtothediagnosisandtreatmentofcyclicvom‐itingsyndrome:alargesingle‐centerexperiencewith106patients.Pediatr Neurol. 2014;50:569‐573.
14. NaminF,PatelJ,LinZ,etal.Clinical,psychiatricandmanometricprofileofcyclicvomitingsyndromeinadultsandresponsetotricy‐clic therapy. Neurogastroenterol Motil. 2007;19:196‐202.
15. Sezer OB, Sezer T. A New Approach to the Prophylaxis ofCyclic Vomiting: Topiramate. J Neurogastroenterol Motil. 2016;22:656‐660.
16. CristoforiF,ThaparN,SaliakellisE,etal.Efficacyof theneuroki‐nin‐1 receptor antagonist aprepitant in children with cyclical vomit‐ing syndrome. Aliment Pharmacol Ther. 2014;40:309‐317.
17. ClouseRE,SayukGS,LustmanPJ,PrakashC.Zonisamideorleveti‐racetamforadultswithcyclicvomitingsyndrome:acaseseries.Clin Gastroenterol Hepatol. 2007;5:44‐48.
18. Jensen AD. Challenges With Acute Care and Response toTreatmentAmongAdultPatientsWithCyclicVomitingSyndrome.Gastroenterol Nurs. 2015;38:469‐476.
19. LeeLY,AbbottL,MahlanguB,MoodieSJ,AndersonS.Theman‐agement of cyclic vomiting syndrome: a systematic review.Eur J Gastroenterol Hepatol. 2012;24:1001‐1006.
20. Hejazi RA, Lavenbarg TH, Foran P,McCallum RW.Who are thenonresponders to standard treatment with tricyclic antidepressant agents for cyclicvomiting syndrome inadults?Aliment Pharmacol Ther. 2010;31:295‐301.
21. HikitaT,KodamaH,KanekoS,etal.Sumatriptanasatreatmentforcy‐clic vomiting syndrome: a clinical trial. Cephalalgia. 2011;31:504‐507.
22. DerryCJ,DerryS,MooreRA.Sumatriptan(all routesofadminis‐tration)foracutemigraineattacksinadults‐overviewofCochranereviews. Cochrane Database Syst Rev.2014;????:CD009108.
23. LiBU,MurrayRD,HeitlingerLA,RobbinsJL,HayesJR.Iscyclicvom‐itingsyndromerelatedtomigraine?J Pediatr. 1999;134:567‐572.
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